Pyridyl Non-Aromatic Nitrogen-Containing Heterocyclic-1-Carboxylate Compound

ABSTRACT

A novel pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound and its pharmaceutically acceptable salt has a potent FAAH-inhibitory activity. Further, the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of the present disclosure is also useful in the treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain.

This is a continuation application of application Ser. No. 11/816,508,filed on Aug. 16, 2007, claiming the benefit of the filing dates ofJapanese Patent Application No. 2005-303065, filed Oct. 18, 2005, andJapanese Patent Application No. 2005-040917, filed Feb. 17, 2005. Allapplications cited in this paragraph are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a pyridyl non-aromaticnitrogen-containing heterocyclic-1-carboxylate derivative or itspharmaceutically acceptable salt, serving as a medicine, especially as aremedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain having a fatty acid amidehydrolase (hereinafter referred to as FAAH)-inhibitory activity. Thepresent invention also relates to a screening method for an FAAHactivity inhibitor serving as a remedy for urinary frequency and urinaryincontinence, a remedy for overactive bladder and/or a remedy for pain;and to a pharmaceutical composition for treatment of urinary frequencyand urinary incontinence, for treatment of overactive bladder and/or fortreatment of pain that contains the substance obtained according to thescreening method of the present invention or contains a substance whichinhibits the activity of fatty acid amide hydrolase.

BACKGROUND ART

Fatty acid amide hydrolase (FAAH) is known to hydrolyze endocannabinoidto inactivate it (see Non-Patent References 1 to 4). Endocannabinoid isa generic term for a biological substance that acts on a cannabinoidreceptor to exhibit its physiological activity. Typical endocannabinoidsare anandamide, palmitoyl ethanolamide, oleamide, 2-arachidonoylglycerol; and they are known to be hydrolyzed by FAAH to lose theiractivity. Δ9-tetrahydrocannabinol that is considered as the activeingredient of Cannabis (marijuana) is known to activate a cannabinoidreceptor (see Non-Patent Reference 5).

In mammals, two types of cannabinoid receptor CB1 and CB2 haveheretofore been known. CB1 is expressed in central and peripheralnervous systems, and when activated, it exhibits its mental action andanalgesic action. CB2 is expressed in immune systems, and whenactivated, it exhibits its antiinflammatory action and analgesic (andantiinflammatory) action.

On the other hand, in a cystitic rat model, a cannabinoid receptoragonist increases the bladder capacity and the urination threshold(Non-Patent Reference 6 and Non-Patent Reference 7); and the sideeffects of hallucination, delusion, tachycardia, orthostatic hypotensionto be observed in administration of a cannabinoid receptor agonist toanimals are not observed when an FAAH inhibitor is administered thereto(Non-Patent Reference 8). From these, the FAAH inhibitor is expected asa remedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain.

As compounds having an FAAH-inhibitory activity, known are compoundscapable of serving as analgesic, antianxiety, antiepileptic,antidepressant, antiemetic, cardiovascular agent or antiglaucomatousagent [C1-4 alkyl or polycyclic aromatic ester derivatives of aromaticring or phenyl-substituted aliphatic hydrocarbon-carbamic acids (PatentReference 1) and phenyl cyclohexylcarbamate (Patent Reference 2)].Dioxane-2-alkylcarbamate derivatives, which are compounds having anFAAH-inhibitory activity, are described as a remedy for urinaryincontinence, one embodiment of a large number of disorders listedtherein (Patent Reference 3). However, Patent Reference 3 does notdisclose experimental results to support the remedial effect fortreatment of urinary frequency and urinary incontinence and/or fortreatment of overactive bladder, not disclosing any suggestion for it.4-Aminopyridyl piperidine-1-carboxylate, a type of pyridyl non-aromaticnitrogen-containing heterocyclic-1-carboxylates, is described as anacetylcholine esterase inhibitor (Non-Patent Reference 9); however, thereference describes nothing about the compound to be a remedy forurinary frequency and urinary incontinence and/or a remedy foroveractive bladder.

Patent Reference 1: WO2003/065989

Patent Reference 2: WO2004/033422

Patent Reference 3: JP-A 2003-192659

Non-Patent Reference 1: Prostaglandins Leukotrienes and Essential FattyAcids, (England), 2002, Vol. 66, pp. 143-160

Non-Patent Reference 2: British Journal of Pharmacology (England), 2004,Vol. 141, pp. 253-262

Non-Patent Reference 3: Nature (England), 1996, Vol. 384, pp. 83-87

Non-Patent Reference 4: Biochemical Pharmacology, (USA), 2001, Vol. 62,pp. 517-526

Non-Patent Reference 5: Current Medicinal Chemistry (USA), 1999, Vol. 6,pp. 635-664

Non-Patent Reference 6: The Journal of Neuroscience, 2002, Vol. 22, pp.7147-7153

Non-Patent Reference 7: Pain, 1998, Vol. 76, pp. 189-199

Non-Patent Reference 8: Nature Medicine, (England), 2003, Vol. 9, pp.76-81

Non-Patent Reference 9: Journal of Pharmaceutical Science, 1992, Vol.81, pp. 380-385

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a remedy for urinaryfrequency and urinary incontinence, a remedy for overactive bladderand/or a remedy for pain, which are free from or are relieved fromcannabinoid-like side effects and a problem of addiction. Other objectsare to provide a method for screening for an FAAH activity-inhibitingsubstance, or that is, a remedy for urinary frequency and urinaryincontinence, a remedy for overactive bladder and/or a remedy for pain;and to provide a pharmaceutical composition for treatment of urinaryfrequency and urinary incontinence, for treatment of overactive bladderand/or for treatment of pain, which contains the substance obtainedaccording to the screening method of the present invention or asubstance capable of inhibiting the activity of a fatty acid amidehydrolase.

Means for Solving the Problems

The present inventors have assiduously studied for producing a compoundhaving an FAAH-inhibitory activity, and as a result, have found outnovel pyridyl nitrogen-containing heterocyclic-1-carboxylatederivatives.

In addition, the present inventors have found for the first time that,when a compound having an FAAH-inhibitory activity is administered to arat suffering from urinary frequency induced by cyclophosphamide, thenthe effective bladder capacity of the rat increases, and have furtherfound that the compound having an FAAH-inhibitory activity has anexcellent therapeutical effect in a pain model rat, therefore providinga screening method for a remedy for urinary frequency and urinaryincontinence, a remedy for overactive bladder and/or a remedy for painby selecting an FAAH inhibitor, and have thus completed the presentinvention.

Specifically, the present invention relates to the following:

[1] A pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate derivative of a general formula (I), and itspharmaceutically acceptable salt:

[the symbols in formula (I) have the following meanings:HET¹ represents a 5- to 7-membered non-aromatic nitrogen-containinghetero ring,R¹, R² and R³ are the same or different, each representing

(1) H,

(2) OH,

(3) optionally-esterified carboxyl,

(4) cyano,

(5) lower alkyl-CO—,

(6) oxo (═O),

(7) a formula [R¹⁰¹—(O)m1]m2-[ALK¹ optionally substituted withOH]—(O)n1-,

-   -   (m1 and n1 are the same or different, each indicating 0 or 1,    -   m2 is from 1 to 5,    -   ALK¹ represents lower alkylene, lower alkenylene or lower        alkynylene,    -   R¹⁰¹ represents        -   (i) H,        -   (ii) Ar^(1a) optionally substituted with at least one            substituent selected from the group consisting of:            -   (a) H₂N—,            -   (b) halo,            -   (c) cyano,            -   (d) optionally-esterified carboxyl,            -   (e) a group R^(1011a)R^(1012a)NCO—,            -   (f) HET²,            -   (g) Ar^(1a) optionally substituted with halo, cyano, OH,                lower alkyl-O— or lower alkyl,                -   Ar^(1a) represents aryl,            -   (h) lower alkyl,            -   (j) OH,            -   (k) lower alkyl-O— optionally substituted with Ar^(1a)                or halo-Ar^(1a),            -   (l) HET²-CO— optionally substituted with halo, Ar^(1a)                or HETAr^(1a),                -   HET² represents nitrogen-containing hetero ring,                -   HETAr^(1a) represents nitrogen-containing                    heteroaryl,            -   s) HET²-CONR^(1011a)—,            -   (t) H₂NCONH—, and            -   (u) optionally-esterified carboxyl-ALK^(2a),                -   ALK^(2a) represents lower alkyl or lower alkenyl,        -   (iii) ALK^(2a) optionally substituted with a group            R^(1011a)R^(1012a)N or Ar^(1a),            -   R^(1011a) and R^(1012a) are the same or different, each                representing                -   (a) H,                -   (b) cALK,                -    cALK represents a cycloalkyl,                -   (c) ALK^(2a) optionally substituted with halo, cALK,                    OH, lower alkyl-O— or Ar^(1a), or                -   (d) Ar^(1a)—SO₂— optionally substituted with halo,        -   (iv) HET² optionally substituted with at least one            substituent selected from the group consisting of            -   (a) ALK^(2a) optionally substituted with Ar^(1a) or                halo-Ar^(1a),            -   (b) Ar^(1a),            -   (c) HETAr^(1a) optionally substituted with lower alkyl,            -   (d) Ar^(1a)—CO— or halo-Ar^(1a)—CO—,        -   (v) cALK optionally substituted with ALK^(2a),        -   or        -   (vi) optionally-esterified carboxyl,        -   (in this, when m2 is from 2 to 5, then [R¹⁰¹—(O)m1]'s may be            the same or different),

(8) a group R¹⁰²-ALK¹⁻N(R¹⁰³)—CO—,

-   -   (R¹⁰² represents        -   (i) H,        -   (ii) cALK,        -   (iii) HETAr^(1a), or        -   (iv) Ar^(1a) optionally substituted with at least one            substituent selected from the group consisting of            -   (a) HO,            -   (b) ALK^(2a)—O—            -   (c) cALK-ALK¹—O—,            -   (d) cALK—Ar^(1a)-ALK¹—O—, and            -   (e) Ar^(1a)-ALK¹—O—,    -   R¹⁰³ represents        -   (i) H,        -   (ii) cALK,        -   (iii) ALK^(2a) optionally substituted with at least one            substituent selected from the group consisting of            -   (a) HET²,            -   (b) Ar^(1a), and            -   (c) halo-Ar^(1a),        -   (iv) HETAr^(1a), or        -   (v) Ar^(1a)—[CO]m1 optionally substituted with at least one            substituent selected from the group consisting of            -   (a) cALK,            -   (b) H₂N,            -   (c) a group R^(1011a)R^(1012a)N—CO—, or            -   (d) ALK^(2a)),

(9) a group R^(104a)R^(105a)N—[CO]m1ALK¹—,

-   -   (R^(104a) and R^(105a) are the same or different, each        representing a group R¹⁰³),

(10) a group R¹⁰⁶-ALK³-L¹-,

-   -   (R¹⁰⁶ represents        -   (i) a group R¹⁰¹—(O)m1-,        -   (ii) a group R^(104a)R^(105a)N—        -   (iii) a group ALK^(2a)—CONH—, or        -   (iv) a group Ar^(1a)—CONH—,    -   ALK³ represents lower alkylene, lower alkenylene or        cycloalkylene,    -   L¹- represents —C(═O)— or —SO₂—),

(11) ALK^(2a)—CONH— optionally substituted with Ar^(1a),

(12) Ar^(1a) substituted with halo,

(13) a group [R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-,

-   -   (Ar² represents arylene,    -   R¹⁰⁷ represents        -   (i) H,        -   (ii) halo,        -   (iii) ALK^(2a) optionally substituted with at least one            substituent selected from the group consisting of            -   (a) HO,            -   (b) cALK,            -   (c) HET²,            -   (d) Ar^(1a) optionally substituted with halo, lower                alkyl, lower alkyl-O—, a group                R^(1011a)R^(1012a)N—[CO]p-, cyano or                optionally-esterified carboxyl,            -   (e) optionally-esterified carboxyl,            -   (f) HET²-[CO]p- optionally substituted with a group                R^(1011a)R^(1012a)N—[CO]p-, and            -   (g) a group R^(1011a)R^(1012a)N—[CO]p-,                -   p indicates 0 or 1,        -   (iv) a group R^(1011a)R^(1012a)N—[CO]p-, or        -   (v) a group R^(1011a)R^(1012a)N—[CO]p-Ar^(1a), in this, when            m2 is from 2 to 5, then [R¹⁰⁷—(O)m1]'s may be the same or            different, and further the group [R¹⁰⁷—(O)m1]m2 may be            methylenedioxy to form a ring),

(14) a group [R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰⁷—(O)m1]'s may be the        same or different),

(15) a group [R^(1011a)R^(1012a)N—[CO]m1]m2-Ar²—(O)n1-,

-   -   (in this, when m2 is from 2 to 5, then        [R^(1011a)R^(1012a)N—[CO]m1]'s may be the same or different),

(16) a group [R¹⁰⁸]m2-Ar²-L²-,

-   -   [R¹⁰⁸ represents        -   (i) H,        -   (ii) halo,        -   (iii) HO,        -   (iv) cALK-O—,        -   (v) a group R¹⁰⁹-ALK¹—(O)m1-,            -   (R¹⁰⁹ represents                -   (a) H,                -   (b) cALK,                -   (c) Ar^(1a) optionally substituted with at least one                    substituent selected from the group consisting of                -    (1′) halo,                -    (2′) cyano,                -    (3′) NO₂,                -    (4′) ALK^(2a) optionally substituted with halo,                -    (5′) HO,                -    (6′) ALK^(2a)—O— optionally substituted with halo,                -    (7′) optionally-esterified carboxyl, or                -    (8′) a group R^(104a)R^(105a)N—,                -   (d) HETAr^(1a), or                -   (e) a group R^(104a)R^(105a)N—[CO]m1-),        -   (vi) a group R¹⁰¹³R¹⁰¹⁴N—,            -   R¹⁰¹³ and R¹⁰¹⁴ are the same or different, each                representing                -   (i) H,                -   (ii) ALK^(2a),                -   (iii) cALK-ALK¹—, or                -   (iv) Ar^(1a)-ALK¹— optionally substituted with at                    least one substituent selected from the group                    consisting of                -    (1′) halo,                -    (2′) cyano,                -    (3′) ALK^(2a) optionally substituted with halo,                -    (4′) ALK^(2a)—O— optionally substituted with halo,        -   (vii) HET²-(O)m1- optionally substituted with lower alkyl,    -   L² represents —CO— or —S(O)_(q)—,        -   q indicates 0, 1 or 2,    -   in this, when m2 is from 2 to 5, then [R¹⁰⁸]'s may be the same        or different],

(17) a group [R¹⁰¹]m2-Ar²—CONH—,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰¹]'s may be the same        or different),

(18) a group [R¹¹¹]m2-HETAr²—(O)m1-,

-   -   (R¹¹¹ represents        -   (i) H,        -   (ii) halo,        -   (iii) oxo (═O), or        -   (iv) a group R^(103a)—(O)n1-,            -   R^(103a) represents                -   (i) H,                -   (ii) cALK,                -   (iii) ALK^(2a) optionally substituted with at least                    one substituent selected from the group consisting                    of                -    (a) HET²,                -    (b) Ar^(1a),                -    (c) cALK and                -    (d) halo-Ar^(1a),                -   (iv) HETAr^(1a), or                -   (v) Ar^(1a) optionally substituted with at least one                    substituent selected from the group consisting                    of (a) cALK, (b) H₂N, and (c) a group                    R^(1011a)R^(1012a)N—CO—,                -    HETAr² represents nitrogen-containing                    heteroarylene,                -    in this, when m2 is from 2 to 5, then [R¹¹¹]'s may                    be the same or different),

(19) a formula [R¹¹²]m2-HETAr²—N(R¹⁰³)—CO—,

-   -   (R¹¹² represents        -   (i) H,        -   (ii) cALK,        -   (iii) ALK^(2a), or        -   (iv) Ar^(1a) optionally substituted with at least one            substituent selected from the group consisting of            -   (a) halo,            -   (b) HO,            -   (c) ALK^(2a)—O—, and            -   (d) Ar^(1a)-ALK¹—O—,        -   in this, when m2 is from 2 to 5, then [R¹¹²]'s may be the            same or different,

(20) a formula [R¹⁰⁸]m2-HETAr²-L²-,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰⁸]'s may be the same        or different), provided that, when any one group of R¹, R² and        R³ is a group [R¹¹¹]m2-HETAr²—(O)m1- and when m1 is 0, then the        remaining groups of R¹, R² and R³ are H;        R⁴, R⁵, R⁶ and R⁷ are the same or different, each representing

(1) H,

(2) halo,

(3) optionally-esterified carboxyl,

(4) HO,

(5) a group R¹¹³-ALK⁴—(O)m3-,

-   -   (ALK⁴ represents lower alkylene, lower alkenylene, or lower        alkynylene, m3 indicates 0 or 1,    -   R¹¹³ represents        -   (i) H,        -   (ii) HO,        -   (iii) lower alkyl-O— optionally substituted with            optionally-esterified carboxyl,        -   (iv) optionally-esterified carboxyl,        -   (v) lower alkyl-CO—O—, or        -   (vi) a group R^(104b)R^(105b)N—[CO]m3-(R^(104b) and R^(105b)            are the same or different, each representing a group R¹⁰³),

(6) R¹¹⁴R¹¹⁵N(R¹¹⁴ and R¹¹⁵ are the same or different, each representing

-   -   (i) H, or    -   (ii) ALK^(2b) optionally substituted with a group        R^(104b)R^(105b)N,        -   ALK^(2b) represents lower alkyl or lower alkenyl),

(7) a group R¹¹⁶-(ALK⁴)n2-N(R¹¹⁷)—CO—,

-   -   (n2 indicates 0 or 1,    -   R¹¹⁶ represents        -   (i) H,        -   (ii) HO,        -   (iii) lower alkyl-O—,        -   (iv) optionally-esterified carboxyl,        -   (v) a group R^(104b)R^(105b)N—[CO]m3-,        -   (vi) Ar^(1b) optionally substituted with (a) OH or (b)            ALK^(2b)—O—,            -   Ar^(1b) represents aryl,        -   (vii) HET³ optionally substituted with a group            R^(104b)R^(105b)N—[CO]m3- or optionally-esterified carboxyl,            -   HET³ represents nitrogen-containing hetero ring,        -   (viii) Ar^(1b) optionally substituted with a group            R^(104b)R^(105b)N—[CO]m3-, or        -   (ix) SO₃H),    -   R¹¹⁷ represents (i) H or (ii) ALK^(2b) optionally substituted        with Ar^(1b),

(8) Ar^(1b) optionally substituted with at least one substituentselected from the group consisting of optionally-esterified carboxyl anda group R^(1011b)R^(1012b)N—[(CO)]m3-,

-   -   R^(1011b) and R^(1012b) are the same or different, each        representing        -   (i) H,        -   (ii) cALK,        -   (iii) ALK^(2b) optionally substituted with halo, cALK, OH,            lower alkyl-O— or Ar^(1b), or        -   (iv) Ar^(1b)—SO₂— optionally substituted with halo,

(9) HET³ optionally substituted with optionally-esterified carboxyl,

(10) HET³-CO— optionally substituted with at least one substituentselected from the group consisting of ALK^(2b) and a groupR^(104b)R^(105b)N—[CO]m3-, or

(11) cyano,

provided that 4-aminopyridin-3-yl piperidine-1-carboxylate isexcluded—the same shall be applied hereinunder].[2] The compound of [1], represented by a general formula (II):

[in formula (II), R¹ to R⁷ have the same meanings as in [1],T represents CH₂, NH, NHCH₂ or O,and this includes a case where the hydrogen in T is substituted with R¹to R³—the same shall be applied hereinunder].[3] The compound of [2], wherein R¹ to R³ are the same or different,each representing a group [R¹⁰¹—(O)m1]m2-[ALK¹ optionally substitutedwith OH]—(O)n1-, a group R¹⁰²-ALK¹—N(R¹⁰³)—CO—, a group R¹⁰⁶-ALK³-L¹-, agroup [R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-, a group [R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—,or a group [R¹⁰⁸]m2-Ar²-L²-.[4] A pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate derivative of a general formula (III) and itspharmaceutically acceptable salt:

[the symbols in formula (III) have the following meanings:ring A represents benzene ring, cyclopentane ring, cyclohexane ring,cycloheptane ring, or 5- to 7-membered nitrogen-containing hetero ring;L represents single bond, lower alkylene, lower alkenylene,—N(R¹⁵)—C(═O)—, —C(═O)—N(R¹⁵)—, -(lower alkenylene)-C(═O)—, —O—, or—C(═O)—,R¹⁵ represents H, or lower alkyl,X represents CH, or N,R⁸ to R¹⁰ are the same or different, each representing

a group selected from the following group G,

aryl optionally substituted with the same or different groups selectedfrom the following group G,

nitrogen-containing heteroaryl optionally substituted with the same ordifferent groups selected from the following group G,

R¹⁶-(lower alkylene)-O—,

R¹⁶-(lower alkylene)-N(R¹⁵)—, or

R¹⁷R¹⁸N—C(═O)—,

R¹⁶ represents

aryl optionally substituted with the same or different groups selectedfrom the following group G,

nitrogen-containing heteroaryl optionally substituted with the same ordifferent groups selected from the following group G, or

3- to 8-membered cycloalkyl,

R¹⁷ and R¹⁸— are the same or different, each representing H, loweralkyl, or 3- to 8-membered cycloalkyl,(further, R¹⁷ and R¹⁸ may form, together with the N atom bondingthereto, 3- to 8-membered nitrogen-containing hetero ring),the group G includes H, halo, —CN, —CF₃, lower alkyl, or —O-lower alkyl,R¹¹ represents H, lower alkyl, or oxo (═O),R¹² to R¹⁴ are the same or different, each representing H, lower alkyl,—C(═O)—O-(lower alkyl), —CO₂H, or —CONH₂].[5] The compound of [4], wherein the ring A is benzene ring, cyclohexanering, piperidine ring, or piperazine ring.[6] The compound of [5], wherein R⁹, R¹⁰, R¹¹, R¹² and R¹³ are H.[7] A pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate of a general formula (IV) and itspharmaceutically acceptable salt:

[the symbols in formula (IV) have the following meanings:ring A¹ represents benzene ring, piperidine ring or piperazine ring;L¹ represents lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, or —O—;R¹⁵ represents H, or lower alkyl,R¹⁹ represents

a group selected from the following group G,

nitrogen-containing heteroaryl optionally substituted with the same ordifferent groups selected from the following group G,

R¹⁶-(lower alkylene)-O—, or R¹⁷R¹⁸N—C(═O)—,

R¹⁶ represents

aryl optionally substituted with the same or different groups selectedfrom the following group G,

nitrogen-containing heteroaryl optionally substituted with the same ordifferent groups selected from the following group G, or

3- to 8-membered cycloalkyl,

R¹⁷ and R¹⁸ are the same or different, each representing H, or loweralkyl, (further, R¹⁷ and R¹⁸ may form, together with the N atom bondingthereto, 5- or 6-membered nitrogen-containing hetero ring),the group G includes H, halo, —CN, —CF₃, lower alkyl, or —O-lower alkyl,R²⁰ represents H, —C(═O)—O-(lower alkyl), —CO₂H, or —CONH₂].[8] A pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate of a general formula (V) and itspharmaceutically acceptable salt:

[the symbols in formula (V) have the following meanings:L² represents lower alkylene, lower alkenylene, or -(loweralkenylene)-C(═O)—,R²¹ represents H, halo, —CN, —CF₃, lower alkyl, or —O-lower alkyl,R²² represents H, —C(═O)—O-(lower alkyl), —CO₂H or —CONH₂].[9] The compound of [1] selected from the following group:

-   pyridin-3-yl    4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate,-   5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic    acid,-   5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid,-   5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic    acid,-   5-[({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic    acid,-   5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic    acid,-   5-(aminocarbonyl)pyridin-3-yl    4-{2-[3-(aminocarbonyl)phenyl]ethyl}piperidine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-(2-{3-[(dimethylamino)carbonyl]phenyl}ethyl)piperidine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-{2-[3-(piperidin-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-{2-[3-(pyrrolidin-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate,    pyridin-3-yl 4-[(2E)-3-phenylprop-2-enoyl]piperazine-1-carboxylate,    pyridin-3-yl 4-(anilinocarbonyl)piperidine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-(2-phenylethyl)piperidine-1-carboxylate, pyridin-3-yl    4-(2-phenylethyl)piperazine-1-carboxylate,-   5-(methoxycarbonyl)pyridin-3-yl    4-(2-phenylethyl)piperazine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-[2-(3-fluorophenyl)ethyl]piperidine-1-carboxylate,-   5-(aminocarbonyl)pyridin-3-yl    4-[2-(3-cyanophenyl)ethyl]piperidine-1-carboxylate.    [10] A pharmaceutical composition comprising the compound of [1] as    an active ingredient thereof.    [11] The pharmaceutical composition of [10], which is an FAAH    inhibitor.    [12] The pharmaceutical composition of [10], which is a medicament    for treatment of urinary frequency, urinary incontinence and/or    overactive bladder.    [13] The pharmaceutical composition of [10], which is a medicament    for treatment of pain.    [14] Use of the compound of [1] for the manufacture of an FAAH    inhibitor or a medicament for treatment of urinary frequency,    urinary incontinence and/or overactive bladder.    [15] Use of the compound of [1] for the manufacture of an FAAH    inhibitor or a medicament for treatment of pain.    [16] A method for treating urinary frequency, urinary incontinence    and/or overactive bladder, comprising administering a    therapeutically effective amount of the compound of [1] to a    patient.    [17] A method for treating pain, comprising administering a    therapeutically effective amount of the compound of [1] to a    patient.    [18] A screening method for a remedy for urinary frequency and    urinary incontinence, a remedy for overactive bladder and/or a    remedy for pain, comprising (1) a step of contacting a test    substance with a polypeptide, which contains (a) an amino acid    sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ    ID NO:8, (b) an amino acid sequence derived from the amino acid    sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ    ID NO:8 through deletion, substitution and/or insertion of from 1 to    10 amino acids therein, (c) an amino acid sequence having a homology    of at least 70% to the amino acid sequence represented by SEQ ID    NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) an amino acid    sequence of the entire amino acid sequence encoded by a    polynucleotide represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5    or SEQ ID NO:7 or by a polynucleotide capable of hybridizing with    its complementary sequence under a stringent condition, or its part    not having at least the transmembrane region-containing amino    terminal region thereof, and which may hydrolyze a substrate, (2) a    step of analyzing the polypeptide for its activity change, and (3) a    step of selecting a substance capable of inhibiting the polypeptide    activity,    (wherein the “substrate” with which FAAH or functional FAAH is    contacted may be any and every endocannabinoid capable of being    hydrolyzed by FAAH or functional FAAH; and concretely, it includes    anandamide, palmitoylethanolamide, 2-arachidonoyl glycerol, and    oleamide; and the substrate labeled with ³H or ¹⁴C, as well as a    mixture of the labeled substrate and the unlabeled substrate may be    used—the same shall be applied hereinunder).    [19] A screening method for a remedy for urinary frequency and    urinary incontinence, a remedy for overactive bladder and/or a    remedy for pain, comprising (1) a step of contacting a test    substance with a polypeptide, which contains (a) an amino acid    sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ    ID NO:8, (b) an amino acid sequence derived from the amino acid    sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ    ID NO:8 through deletion, substitution and/or insertion of from 1 to    10 amino acids therein, (c) an amino acid sequence having a homology    of at least 70% to the amino acid sequence represented by SEQ ID    NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) an amino acid    sequence of the entire amino acid sequence encoded by a    polynucleotide represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5    or SEQ ID NO:7 or by a polynucleotide capable of hybridizing with    its complementary sequence under a stringent condition, or its part    not having at least the transmembrane region-containing amino    terminal region thereof, and which may hydrolyze a substrate, in the    presence of a substrate of the polypeptide, (2) a step of measuring    the amount of the hydrolyzed product converted from the substrate,    and (3) a step of selecting a substance capable of inhibiting the    hydrolysis of the substrate.    [20] A screening method for a remedy for urinary frequency and    urinary incontinence, a remedy for overactive bladder and/or a    remedy for pain, comprising (1) a step of contacting a test    substance with a cell or a tissue expressing a polypeptide, which    contains (a) an amino acid sequence represented by SEQ ID NO:2, SEQ    ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, (b) an amino acid sequence    derived from the amino acid sequence represented by SEQ ID NO:2, SEQ    ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 through deletion, substitution    and/or insertion of from 1 to 10 amino acids therein, (c) an amino    acid sequence having a homology of at least 70% to the amino acid    sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ    ID NO:8, or (d) an amino acid sequence of the entire amino acid    sequence encoded by a polynucleotide represented by SEQ ID NO:1, SEQ    ID NO:3, SEQ ID NO:5 or SEQ ID NO:7 or by a polynucleotide capable    of hybridizing with its complementary sequence under a stringent    condition, or its part not having at least the transmembrane    region-containing amino terminal region thereof, and which may    hydrolyze a substrate, or with a lysate or a homogenate of the cell    or the tissue, in the presence of a substrate of the    polypeptide, (2) a step of measuring the amount of the hydrolyzed    product converted from the substrate, and (3) a step of selecting a    substance capable of inhibiting the hydrolysis of the substrate.    [21] A screening method for a remedy for urinary frequency and    urinary incontinence, a remedy for overactive bladder and/or a    remedy for pain, comprising (1) a step of contacting a test    substance with a fatty acid amide hydrolase, (2) a step of analyzing    the enzyme for its activity change, and (3) a step of selecting a    substance capable of inhibiting the activity of the enzyme.

OUTCOMES OF THE INVENTION

The pharmacological tests of Examples 438 to Example 442 have confirmedthe effectiveness of the compounds of the present invention. Forexample, typical compounds shown in Table 64 have an excellentFAAH-inhibitory effect; typical compounds shown in Example 441 areuseful as a remedy for urinary frequency and urinary incontinence, and aremedy for overactive bladder; and typical compounds shown in Example442 are useful as a remedy for pain. In addition, the compounds of thepresent invention are highly stable in aqueous solutions, and haveexcellent properties as medicines.

The invention described in Patent Reference 2 is useful as analgesic,antianxiety, antiepileptic, antidepressant, antiemetic, cardiovascularagent or antiglaucomatous agent; however, the present inventors havefound that the present invention is useful for a remedy for urinaryfrequency and urinary incontinence and/or a remedy for overactivebladder, differing from Patent Reference 2. Further, the compounds ofthe present invention have an excellent FAAH-inhibitory effect, and aretherefore useful for remedies for (1) neuropsychiatric disorders (e.g.,anxiety, depression, epilepsy), (2) brain disorders, neurodegenerativedisorders (e.g., head injury, cerebral ischemia, dementia), (3)immunological and inflammatory diseases, (4) vomiting, (5) eatingdisorders, (6) irritable bowel syndrome, ulcerative colitis, (7)hypertension, (8) glaucoma, or (9) sleep disorders. In addition, thecompounds are free from or are relieved from cannabinoid-like sideeffects and a problem of addiction.

Further, according to the screening method of the present invention, aremedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain that are free from or arerelieved from cannabinoid-like side effects and a problem of addictioncan be selected on the basis of inhibition of FAAH activity. Thesubstances obtained according to the screening method and the FAAHactivity-inhibitory substances may produce pharmaceutical compositionsuseful for treatment of urinary frequency and urinary incontinence, fortreatment of overactive bladder and/or for treatment of pain.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail hereinunder.

The compounds of the present invention are described in detailhereinunder.

DEFINITIONS

Unless otherwise specifically indicated, the term “lower” in thedefinition of the structural formulae in this description means a linearor branched carbon chain having from 1 to 6 carbon atoms.

“Lower alkyl” includes, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, hexyl, isohexyl; preferably methyl, ethyl, propyl, butyl,tert-butyl.

“Lower alkenyl” means an aliphatic hydrocarbon group having at least onedouble bond, including, for example, vinyl, propenyl, allyl,isopropenyl, 1,3-butadienyl, hexenyl.

“Cycloalkyl” means a mono- to tri-cyclic aliphatic saturated hydrocarbonring group having from 3 to 14 carbon atoms, including, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicycloheptyl, bicyclooctyl, tricyclododecanyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, preferably cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

“Aryl” means a mono- to tri-cyclic aromatic hydrocarbon ring grouphaving from 6 to 14 carbon atoms, in which the phenyl may be condensedwith cycloalkyl. For example, it includes phenyl, indenyl, naphthyl,anthryl, phenanthryl, indanyl, tetrahydronaphthyl, preferably phenyl,naphthyl.

“Heterocyclic” means a 4- to 16-membered, monocyclic, bicyclic ortricyclic, saturated or unsaturated ring having from 1 to 4 hetero atomsselected from N, S and O. The heterocyclic group may be crosslinked orspiro-structured. The unsaturated ring includes an aromatic ring(heteroaryl) and a non-aromatic ring. The monocyclic group includesazetidinyl, oxetanyl, pyrrolidinyl, 1,3-dioxolanyl, pyrazolidinyl,piperazinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,pyridyl, pyrazinyl, pyrimidinyl, triazolyl, thiadiazolyl, pyridazinyl,oxadiazolyl, tetrazolyl; the bicyclic group includes indolyl,isoindolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl,benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzimidazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl,1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl,decahydroisoquinolyl, quinoxalinyl; the tricyclic group includescarbazolyl, acridinyl, phenothiazinyl. The crosslinked heterocyclicgroup includes quinuclidinyl, 2,5-diazabicyclo[2.2.1]heptyl,8-azabicyclo[3.2.1]octyl, 7-azabicyclo[2.2.1]heptyl. Thespiro-structured heterocyclic group includes1,4-dioxa-8-azaspiro[4,5]decanyl.

“Nitrogen-containing heteroaryl” means a 4- to 10-membered, mono- orbi-cyclic aromatic nitrogen-containing heteroaryl, having from 1 to 4nitrogen atoms of the above-mentioned heterocyclic group. It includes,for example, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzimidazolyl, benzopyrazolyl, quinolyl, isoquinolyl,quinoxalinyl, preferably imidazolyl, thiazolyl, pyridyl, benzimidazolyl,quinolyl.

“Nitrogen-containing saturated heterocyclic group” means a 3- to10-membered, mono- or bi-cyclic nitrogen-containing heterocycloalkylgroup, having from 1 to 3 nitrogen atoms of the above-mentionedheterocyclic group. It includes, for example, aziridinyl, azetidinyl,pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, hexahydroazepinyl,1,4-diazepinyl, 1,4-oxazepinyl, quinuclidinyl,2,5-diazabicyclo[2.2.1]heptyl, azabicyclooctyl (e.g.,azabicyclo[3.2.1]octyl), diazabicyclooctyl, azabicyclononyl,azabicyclodecanyl, 1,4-dioxa-8-azaspiro[4,5]decanyl, preferablypyrrolidinyl, piperidyl, piperazinyl, morpholinyl, hexahydroazepinyl,1,4-diazepinyl, 1,4-oxazepinyl, quinuclidinyl,2,5-diazabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl.

“Nitrogen-containing hetero ring” means the above-mentionednitrogen-containing heteroaryl group, the above-mentionednitrogen-containing saturated heterocyclic group, or a condensed groupof nitrogen-containing heteroaryl and nitrogen-containingheterocycloalkyl. Preferably, it is pyrrolidinyl, piperidyl,piperazinyl, morpholinyl, hexahydroazepinyl, azabicyclo[3.2.1]octyl,1,4-dioxa-8-azaspiro[4.5]decanyl, imidazolyl, pyridyl, quinolyl.

“Non-aromatic nitrogen-containing hetero ring” means anitrogen-containing saturated heterocyclic group and an unsaturatednitrogen-containing heterocyclic group except the nitrogen-containingheteroaryl of the above-mentioned nitrogen-containing heterocyclicgroup. Preferably, it is a 5- to 7-membered non-aromaticnitrogen-containing heterocyclic group.

“Lower alkylene”, “lower alkenylene”, “cycloalkylene”, “arylene” and“nitrogen-containing heteroarylene” are divalent groups derived from theabove-mentioned lower alkyl, lower alkenyl, cycloalkyl, aryl andnitrogen-containing heteroaryl, by removing any one hydrogen atom fromthem.

“Esterified carboxyl” means lower alkyl-O—CO—, aryl-lower alkyl-O—CO—,or —H₂N—CO-aryl-lower alkyl-O—CO—.

“Halo” means a halogen group, concretely including fluoro, chloro,bromo, iodo, preferably fluoro, chloro.

“Optionally substituted” means “unsubstituted” or “substituted with thesame or different, 1 to 5 substituents”.

Depending on the type of the substituent therein, the compound (I) ofthe present invention may have optical isomers (optically-activeisomers, diastereomers) or geometric isomers. Accordingly, the compound(I) of the present invention includes mixtures or isolated compounds ofthese optical isomers or geometric isomers.

The compound (I) of the present invention may form pharmaceuticallyacceptable salts such as acid-addition salts or salts with bases. Forexample, the salts includes acid addition salts with an inorganic acidsuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, phosphoric acid; or an organic acid such as formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid,tartaric acid, carbonic acid, picric acid, methanesulfonic acid,ethanesulfonic acid, glutamic acid; as well as salts with an inorganicbase such as sodium, potassium, magnesium, calcium, aluminium; or anorganic base such as methylamine, ethylamine, monoethanolamine,diethanolamine, triethanolamine, cyclohexylamine, lysine, ornithine.Further, the compound (I) or its pharmaceutically acceptable salt of thepresent invention may form hydrates, solvates with ethanol or the like,and crystalline polymorphs.

Further, the compound (I) of the present invention includes allcompounds capable of being metabolized in living bodies to be convertedinto the compound (I) or its pharmaceutically acceptable salt of thepresent invention, that is, prodrugs. The group to form prodrugs of thecompound (I) of the present invention includes those described in Prog.Med., 5:2157-2161 (1985), and those described in “PHARMACEUTICALRESEARCH and DEVELOPMENT”, VOLUME 7 Drug Design, pp. 163-198 by HirokawaPublishing, 1990. Concretely, they are groups capable of being convertedinto primary amine or secondary amine, or HO—, HO—CO— or the like in thepresent invention through hydrolysis or solvolysis or under aphysiological condition. Prodrugs of HO— are, for example,optionally-substituted lower alkyl-CO—O—, optionally-substitutedaryl-CO—O—, optionally-substituted heteroaryl-CO—O—,RO—CO-optionally-substituted lower alkylene-CO—O— (R means H— or loweralkyl—the same shall be applied hereinunder),RO—CO-optionally-substituted lower alkenylene-CO—O—, RO—CO-loweralkylene-O-lower alkylene-CO—O—, RO—CO—CO—O—,ROS(═O)₂-optionally-substituted lower alkenylene-CO—O—, phthalidyl-O—,5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy.

“Urinary frequency” as referred to in this description indicates acondition where the urination frequency has increased over a normalrange. “Urinary incontinence” means a involuntary urination that isproblematic in a social and sanitary life.

“Overactive bladder” as referred to in this description indicates asyndrome to be diagnosed by a subjective symptom such as urinaryfrequency or urgency (Neurourology and Urodynamics, USA, 2002, Vol. 21,pp. 167-178). The pathogenic cause includes, for example, neuropathy(for example, caused by neurogenic bladder, cerebral infarction), lowerurinary tract obstruction (e.g., benign prostatic hypertrophy) andaging; and as the pathogenic mechanism common to these, hyperactivity ofcapsaicin-sensitive afferent neuron.

Overactive bladder may be treated by relieving the condition of urinaryfrequency, urinary incontinence and urgency. This is obvious, forexample, from the fact that administration of an anticholinergic agent,oxybutynin hydrochloride (Japan Standard Product Classification Number87259; by Aventis Pharma) to a patient suffering from overactivebladder, at a dose of from 2 to 3 mg/once and three times a day mayrelieve the condition of urinary frequency, urinary incontinence andurgency, and the administration is therefore effective for treatment ofoveractive bladder.

The presence of the effect for treatment of urinary frequency andurinary incontinence and/or the effect for treatment of overactivebladder may be confirmed by methods known to those skilled in the art orby modified methods from them. For example, a pathologic model inducedby administration of from 50 to 200 mg of cyclophosphamide (CPA) to rat,guinea pig, dog or the like is frequently used in this technical field(Ozawa et al., The Journal of Urology, Vol. 162, pp. 2211-2216, 1999;Boucher et al., The Journal of Urology, Vol. 164, pp. 203-208, 2000).This is a pathologic model that accompanies hemorrhagic cystitis, andsince capsaicin-sensitive afferent neuron participates in the pathogenicmechanism of urinary frequency, it may be considered that this model maybe a suitable pathologic model for various types of overactive bladderincluding neuropathic bladder (Carlo Alberto Maggi et al., Journal ofthe Autonomic Nervous System, Vol. 38, pp. 201-208, 1992). A urinaryfrequency condition may be confirmed by the decrease in the effectivebladder capacity. To the pathologic model animal, an effective dose of apharmaceutical composition is administered orally, intraperitoneally orintravenously, once or plural times; and when the effective bladdercapacity of the animal has increased, then the effect of thepharmaceutical composition for treatment of urinary frequency andurinary incontinence and/or for treatment of overactive bladder may beconfirmed.

“Pain” as referred to in this description is a generic term forneuropathic pain, nociceptive pain and inflammatory pain, of which“neuropathic pain” means pain caused by peripheral or central nervoussystem dysfunction and includes diabetic neuropathic pain, cancer pain,trigeminal neuralgia, phantom pain, postherpetic pain and thalamic pain.The essential clinical symptom of neuropathic pain includes pain as ifclutched, pain as if scorched, hyperalgesia and allodynia.

Nonsteroidal antiinflammatory drugs and narcotic analgesics such asmorphine that are ordinary analgesics are known to be weakly effectivefor neuropathic pain. In a medical site, an antiepileptic such asgabapentin, and an antiarrhythmic such as mexiletine are used for painrelief, but their analgesic potency is not sufficient.

The presence of the effect for treatment of neuropathic pain may beconfirmed by methods known to those skilled in the art or by modifiedmethods from them. For example, using an L5/L6 spinal nerve ligated ratthat is produced according to partial modification of a Kim and Chung'smethod (Pain, Vol. 50, pp. 355-363, 1992), the ameliorating effect of acompound for significant reduction in the response threshold to tactilestimulation (allodynia) is evaluated, and based on it, the effect of thetested compound for treatment of neuropathic pain may be confirmed.

The compound of the present invention includes those effective forurinary frequency and urinary incontinence as well as overactivebladder; those effective for pain, especially for neuropathic pain; andthose effective for both the two.

[Production Methods]

The compound and its pharmaceutically acceptable salt of the presentinvention can be produced by applying various known production methods,utilizing the characteristics based on its basic skeleton of thecompound or the type of the substituent therein.

Depending on the type of a functional group in the compound, it mayoften be effective in point of its production technology to substitutethe functional group with a suitable protective group (capable of beingreadily converted into the functional group) in a stage of its startingmaterial or intermediate. The functional group includes, for example, anamino group, a hydroxyl group and a carboxyl group; and their protectivegroups are, for example, those described in “Protective Groups inOrganic Synthesis (2nd Ed)” by Greene & Wuts. These may be suitablyselected and used depending on the reaction conditions.

In this method, the protective groups is removed if necessary after ithas been introduced and the reaction carried out, in order to producethe desired compound.

Typical production methods for the compounds of the present inventionand their intermediates are described below.

(The abbreviations given in the following description are as follows:

-   DMF: N,N-dimethylformamide,-   DMSO: dimethylsulfoxide,-   THF: tetrahydrofuran,-   TFA: trifluoroacetic acid,-   Tol: toluene,-   EtOAc: ethyl acetate,-   DCE: 1,2-dichloroethane,-   TEA: triethylamine)

Typical production methods for the compounds of the present inventiondescribed below, to which, however, the present invention should not belimited.

In case where a similar substituent exists in a site of the compound ofthe present invention except that in the reaction formula in theproduction method for the compound, the compound that is encompassedwithin the scope of the present invention may be readily producedthrough substituent modification.

Production Method 1 (Carbamate Formation):

(In the formula, X represents a leaving group advantageous to thereaction, and the same shall be applied hereinunder.)

This reaction is for esterification of a ketone derivative of a generalformula (VI) and a reaction-corresponding amount of a hydroxypyridinederivative of a general formula (VII), in a solvent inert to thereaction, with stirring with cooling or at room temperature or withheating. The leaving group X includes, for example, a halogen atom, alower alkoxy group, a phenoxy group, an imidazolyl group. The inertsolvent includes, for example, DMF, dimethylacetamide, THF, dioxane,dimethoxyethane, diethoxyethane, benzene, Tol, xylene and their mixedsolvents. For promoting the reaction, a base (e.g., sodium, sodiumhydride, sodium methoxide, sodium ethoxide) is preferably added to thereaction mixture.

Production Method 2 (Carbamate Formation):

This reaction is conducted by stirring a nitrogen-containingheterocyclic compound of a general formula (VIII) and areaction-corresponding amount of a pyridine derivative of a generalformula (IX) in a solvent inert to the reaction, with cooling or at roomtemperature or with heating. For promoting the reaction, a base (e.g.,sodium, sodium hydride, sodium methoxide, sodium ethoxide, TEA,pyridine) is preferably added to the reaction mixture.

Production Method 3 (Hydrolysis):

A compound (1-3) of the present invention having a carboxyl group can beobtained through hydrolysis of the corresponding compound having anesterified carboxyl group, for example, according to deprotectiondescribed in “Protective Groups in Organic Synthesis (2nd Ed)” by Greene& Wuts.

(In the formula, the group ROCO— means an esterified carboxyl group, andthe same shall be applied hereinunder.)

Production Method 4 (Amidation):

The compound (I-3) or the compound where R¹ is a carboxylic acid mayreact with an amine, and the compound where R¹ is an amine may reactwith a carboxylic acid, thereby various amide compounds can be obtained.When the nitrogen-containing heterocyclic compound is piperidine, thenit may be reacted with a carboxylic acid or a sulfonic acid compound ortheir reactive derivative to produce various types of amide compounds.The reaction may be conducted in the presence of a condensing agent(e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC),1,1′-carbonylbis-1H-imidazole (CDI)) and optionally further in thepresence of an additive (e.g., N-hydroxysuccinimide (HONSu)1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP)). Thereactive derivative of the carboxylic acid or the sulfonic acid compoundincludes acid halides, acid anhydrides, active esters. The reaction mayalso be conducted, for example, according to the methods described in“Jikken Kagaku koza (Courses in Experimental Chemistry, 4th Ed)”, Vol.22, edited by the Chemical Society of Japan, Maruzen, 1992.

Production Method 5 (Coupling Reaction):

(In the formula, the symbols have the following meanings. X representshalogen or —O—SO₂CF₃, and Y represents —B(OH)₂, dialkylboron,dialkoxyboron or trialkyltin. X may be —B(OH)₂, dialkylboron,dialkoxyboron or trialkyltin, and Y may be halogen or —O—SO₂CF₃.)

Two aromatic rings, or that is, a combination of a compound (I-6) and acompound (I-7), are reacted preferably in the presence of a transitionmetal catalyst and a suitable additive, thereby producing a biarylcompound (I-8). Typical methods for it are described in “Jikken Kagakukoza (Courses in Experimental Chemistry, 4th Ed)”, Vol. 25, OrganicSynthesis VII, pp. 353-366, pp. 396-427, 1991 (Maruzen). The transitionmetal catalyst preferred for use herein includes various palladiumcomplexes such as tetrakis(triphenylphosphine)palladium, and variousnickel complexes such as dibromobis(triphenylphosphine)nickel. Theadditive also preferred for use herein includes triphenylphosphine,sodium carbonate, zinc; and these may be suitably selected depending onthe method to which they are applied. In general, the reaction isconducted in a solvent at room temperature or with heating. Apart fromthe reaction described herein, also preferably used is a reaction forbiaryl structure formation, for example, a reaction of a halogenatedaryl compound with an aryl-Grignard reagent in the presence of asuitable transition metal catalyst.

(Production Methods for Starting Compounds)

The starting compounds to be used for producing the compounds of thepresent invention may be known compounds or may be produced byoptionally processing known compounds according to the above-mentionedproduction methods, or according to methods well known to those skilledin the art (J. March, ADVANCED ORGANIC CHEMISTRY (John WILEY & SONS(1992)) (for example, acylation, alkylation, urea formation, oxidation,reduction (preferably, COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION(Pergamon Press) (1991)), halogenation).

Production Method (i): Mitsunobu Reaction:

A starting compound (X) may be produced through Mitsunobu reaction ofalcohols of general formulae (XI) and (XII). This reaction is conductedby stirring the compounds (XI) and (XII) in the presence of anequivalent or excessive amount of triphenylphosphine and diethylazodicarboxylate, in an inert solvent as in the production method 1,under cooling to heating conditions.

(In the formula, the symbols have the following meanings:U represents an amino-protective group,ALK³ represents ALK¹ optionally substituted with HO, and the same shallbe applied hereinunder.)

Production Method (ii): Substitution Reaction:

This reaction is alkylation. A primary amine, a secondary amine, analcohol, a thiol, a primary amide or a secondary amide is reacted with areaction-corresponding amount of a compound having a leaving group, in asolvent inert to the reaction, in an equivalent ratio of the two, or insuch a ratio that any one of the two is excessive, with stirring undercooling to heating conditions. As the case may be, the reaction may beconducted advantageously in the presence of a base (e.g., inorganic basesuch as potassium carbonate, sodium carbonate, cesium carbonate; organicbase such as TEA, diisopropylethylamine; metal alkoxide such aspotassium tert-butoxide, sodium tert-butoxide; sodium hydride, lithiumhydride) and an additive (tetra-n-butylammonium iodide, potassiumiodide, sodium iodide) for smoothly promoting the reaction. The solventinert to the reaction includes, for example, dichloromethane, DCE,chloroform, benzene, Tol, xylene, ether, THF, dioxane, EtOAc, ethanol,methanol, 2-propanol, acetonitrile, DMF, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylimidazolidinone, DMSO, acetone, methylethyl ketone, water, as well as their homogeneous or heterogeneous mixedsolvents. The solvent may be suitably selected depending on variousreaction conditions employed.

[In the formula, the symbols have the following meanings:Q represents O, S or NH,Z represents a leaving group (e.g., Cl, Br, I or OMs).]Production Method (iii):

This production method comprises reacting an aldehyde or ketone of ageneral formula (XVI) with a Wittig reagent or a Horner-Emmons reagentof a general formula (XVII), thereby producing a compound (XVI).

This reaction is conducted in the presence of an equivalent or excessiveamount of a base (e.g., organic base such as TEA, diisopropylethylamine;inorganic base such as potassium carbonate, sodium carbonate, cesiumcarbonate), by stirring the compound (XVI) and the compound (XVII) inthe above-mentioned inert solvent, in an equivalent ratio of the two, orin such a ratio that any one of the two is excessive, under cooling toheating conditions. As the case may be, an additive (e.g.,tetra-n-butylammonium iodide, potassium iodide) may be advantageouslyadded to the system for smoothly promoting the reaction.

Z₁ represents a group used in a Wittig reagent or a Horner-Emmonsreagent (e.g., phosphonium salt, or phosphorous diester),

n indicates 0 or 1.

[1] Screening Method of the Present Invention:

Fatty acid amide hydrolase (hereinafter this may be referred to as FAAH)includes enzymes having an activity of hydrolyzing anandamide,palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol, and sofar as they are identified as those of the same molecule species, theymay be derived from any species, for example, from mammals such as human(GenBank Accession Number NM_(—)001441), mouse (GenBank Accession NumberNM_(—)010173), rat (GenBank Accession Number NM_(—)024132), porcine(GenBank Accession Number AB027132), rabbit, sheep, chicken, dog, cat,hamster, squirrel, bear, deer, monkey. In addition, it is not limited toa natural polypeptide, but may include artificially-produced mutants.

Regarding (a) a polypeptide which contains an amino acid sequence of theentire amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQID NO:6 or SEQ ID NO:8 or a part of the amino acid sequence not havingat least the transmembrane region-containing amino terminal regionthereof, and which may hydrolyze anandamide, palmitoylethanolamide,oleamide, and/or 2-arachidonoyl glycerol;

(b) a polypeptide which contains an amino acid sequence of the entireamino acid sequence derived from the amino acid sequence represented bySEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 through deletion,substitution and/or insertion of from 1 to 10, preferably from 1 to 7,more preferably from 1 to 5 amino acids therein, or a part of the aminoacid sequence not having at least the transmembrane region-containingamino acid terminal region thereof, and which may hydrolyze anandamide,palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol;

(c) a polypeptide which contains an amino acid sequence having ahomology of at least 70%, preferably at least 80%, more preferably atleast 90%, most preferably at least 95% to the amino acid sequencerepresented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, andwhich may hydrolyze anandamide, palmitoylethanolamide, oleamide, and/or2-arachidonoyl glycerol;

(d) a polypeptide which contains an amino acid sequence of the entireamino acid sequence encoded by a polynucleotide represented by SEQ IDNO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7 or by a polynucleotidecapable of hybridizing with its complementary sequence under a stringentcondition, or its part not having at least the transmembraneregion-containing amino terminal region thereof, and which may hydrolyzeanandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoylglycerol;

the above (a) to (d) are generically referred to as a generic term“functional FAAH”.

The above-mentioned “transmembrane region-containing amino terminalregion” as referred to in this description means an amino terminalregion that includes the extracellular region at an amino terminal, anda transmembrane region buried in the cell membrane sandwiched betweenthe extracellular region and the intracellular region. The existence andthe site of the transmembrane region may be predicted from the aminoacid sequence of the protein, using a protein membrane structureprediction program, TMpred, PSORT, SOSUI. Concretely, the “transmembraneregion-containing amino terminal region” is, for example, the region offrom the first to the 30th in SEQ ID NO:2, and the region of from thefirst to the 29th in SEQ ID NO:6. It is known that the polypeptiderepresented by the 30th to 579th amino acids in SEQ ID NO:6 excludingthe region of from the 1st to the 29th in SEQ ID NO:6 also has the sameenzymatic activity as that of the polypeptide from which the region isnot excluded (Matthew et al., Biochemistry, Vol. 37, pp. 15177-15178,1998).

The “homology” as referred to in this description means the valuesidentities obtained by the use of the parameters prepared in defaultthrough search with Clustal V program (Higgins & Sharp, Gene, Vol. 73,pp. 237-244, 1998; Thompson et al., Nucleic Acid Res., Vol. 22, pp.4673-7680, 1994). The parameters are as follows:

As pairwise alignment parameters,

K tuple 1

Gap Penalty 3

Window 5

Diagonals Saved 5.

The above-mentioned “stringent condition” for hybridization as referredto in this description means a condition not causing any unspecificbinding. Concretely, for example, the hybridization is effected in asolution comprising 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodiumcitrate, pH 7), 5×Denhardt's solution (0.1% Ficoll 400, 0.1%polyvinylpyrrolidone, 0.1% BSA), modified salmon sperm DNA (50 g/ml),0.1% SDS, and 10% dextran sulfate, under a temperature condition of from37 to 42° C. for about 12 to 18 hours, and then optionally afterpre-washed, this is washed with a washing solution (0.2×SSC, 0.1% SDS)under a temperature condition of from 50 to 60° C.

The above-mentioned “hydrolysis of anandamide, palmitoyl ethanolamide,oleamide and/or 2-arachidonoyl glycerol” as referred to in thisdescription concretely means that, according to the method described inExamples 1 to 4, anandamide (N-arachidonoyl ethanolamine) is decomposedinto arachidonic acid and ethanolamine; palmitoyl ethanolamide(N-palmitoyl ethanolamine) is into palmitic acid and ethanolamine;oleamide (cis-9,10-octadecenamide) is into oleic acid and ammonia, and2-arachidonoyl glycerol is into arachidonic acid and glycerol, throughhydrolysis in a buffer having a pH of from 7 to 9 at 4° C. to 37° C. for30 minutes to 90 minutes.

The screening method of the present invention includes a screeningmethod for a remedy for urinary frequency and urinary incontinence, aremedy for overactive bladder and/or a remedy for pain, comprising (1) astep of contacting a test substance with FAAH or functional FAAH, (2) astep of analyzing it for the activity of FAAH or functional FAAH, and(3) a step of selecting a substance that inhibits the activity of FAAHor functional FAAH.

(1) Step of Contacting Test Substance with FAAH or Functional FAAH:

For contacting a test substance with FAAH or functional FAAH, the testsubstance may be added to any of the following:

a) a cell or a tissue expressing FAAH or functional FAAH,

b) a transformant transformed with an expression vector containing apolynucleotide that encodes FAAH or functional FAAH,

c) a lysate or a homogenate of a) or b),

d) a purified product of FAAH or functional FAAH purified from c),

and incubated for a predetermined period of time; or

e) a tissue homogenate or blood of a test animal to which the testsubstance has been administered may be used.

a) Cell or Tissue Expressing FAAH or Functional FAAH:

Concretely, the cell expressing FAAH or functional FAAH includesneurons, glial cells, epithelial cells, endothelial cells, lymphocytes,macrophages, platelets, mast cells, monocytes, dendritic cells,hepatocytes, renal cells, enterocytes, pancreatic cells, uterine cells,placental cells, bladder cells, prostatic cells, keratinization cells,and muscular cells. So far as they express FAAH or functional FAAH,these cells may be derived from any species; and for example, hereinemployable are cells derived from mammals such as human, mouse, rat,porcine, rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear,deer, monkey.

For the cells, usable are established cell lines; and cells peeled fromor isolated from animal tissues may also be used. The established celllines usable herein include human bladder epithelial cancer-derived cellline 5673 cells, human prostatic cancer-derived cell line PC-3 cells,rat basophilic leukemia cell line RBL-2H3 cells, rat neuroblastoma cellline N18TG2 cells, rat glioma cell line C6 cells, rat macrophage cellline J774 cells, rat adrenal medulla-derived pheochromocytoma cell linePC-12 cells, human monocytic cell line U937 cells, human breast cancercell line MFC-7 cells, human breast cancer cell line EFM-19 cells, humancolon cancer-derived cell line CaCo-2 cells (these cell lines areavailable from American Type Culture Collection (ATCC)), human epidermalkeratinocyte cell line HaCaT cells, and human neuroblastoma cell lineCHP100 cells. Preferred are human bladder epithelial cancer-derived cellline 5673 cells, and rat basophilic leukemia cell line RBL-2H3 cells.

The tissue expressing FAAH or functional FAAH concretely includes brain,bladder, prostate, kidney, liver, testis, muscle, vessel, pancreas,digestive tube, lung, uterus, placenta, skin, lymphocyte, platelet,macrophage, monocyte, mast cell, and prostate. Preferably used arebrain, liver and monocyte. So far as they express FAAH or functionalFAAH, these tissues may be derived from any species. For example,tissues derived from mammals such as human, mouse, rat, porcine, rabbit,sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey may beused.

For determining whether or not a cell or a tissue expresses FAAH orfunctional FAAH, a cell or tissue extract may be used and analyzedthrough western blotting, using an antibody capable of detecting theintended polypeptide, or through PCR (polymerase chain reaction) usingprimers capable of specifically detecting a polynucleotide that encodesthe intended polypeptide. In addition, a lysate or a homogenate of acell or a tissue is reacted with a substrate such as anandamide,palmitoyl ethanolamide, oleamide, and/or 2-arachidonoyl glycerol, in abuffer having a pH of from 7 to 9 at 4° C. to 37° C. for 30 minutes to90 minutes, whereupon the system is determined whether or not thesubstrate is hydrolyzed for the intended determination.

b) Transformant Transformed with Expression Vector ContainingPolynucleotide that Encodes FAAH or Functional FAAH:

A polynucleotide that encodes FAAH or functional FAAH may be isolatedfrom a cDNA library through screening by PCR or hybridization, usingprimers and a probe planned and synthesized on the basis of theinformation of known amino acid sequences and base sequences.

The fragment that contains the isolated polynucleotide is inserted intoa suitable expression vector, and it may be transfected into a host cellof eukaryote or prokaryote; and in the host cell, the polypeptideencoded by the transfected polynucleotide may be thus expressed. Theexpression vector may be any known one suitably selected depending onthe host cell, for which, in addition, also usable is a vector plasmidsuitably selected depending on the host cell and having a suitablepromoter and a phenotype expression-related sequence introducedthereinto. Also usable is an expression vector with a specific sequenceintroduced thereinto in such a manner that the polypeptide encoded bythe inserted polynucleotide may be expressed as fused withglutathion-S-transferase (GST) or with a tag such as Flag or His. Incase where one cell is transformed with some different types ofpolynucleotides at the same time, then one expression vector to be usedmay be so planned that it includes such different types ofpolynucleotides, or those polynucleotides may be separately in differentexpression vectors. Alternatively, a cell with a chromosomal DNA havingthe constitution of the type may be produced and it may be used.

The expression vector with a desired polynucleotide introduced thereintomay be given to a host cell according to a DEAE-dextran method (Luthmanet al., Nucleic Acids Res., Vol. 11, pp. 1295-1308, 1983), a calciumphosphate-DNA coprecipitation method (Graham et al., Virology, Vol. 52,pp. 456-457, 1973), a method of using a commercially-availabletransfection reagent, Lipofectamine 2000 (by Invitrogen) or FeGENE 6 (byRoche Molecular Biochemicals), or an electroporation method (Neumann etal., EMBO J., Vol. 1, pp. 841-845, 1982) for intended transformation. Incase where E. coli is used as the host cell, a competent cell of E. coliis formed with coexistence with CaCl₂, MgCl₂ or RbCl according to aHanahan's method (Hanahan et al., Mol. Biol. Vol. 166, pp. 557-580,1983), and an expression vector with the desired polynucleotideintroduced thereinto is given thereto for transformation of the cell.

c) Lysate or Homogenate of a) or b):

A cell homogenate may be prepared by washing a cell a few times with abuffer, and then homogenized using a Potter-Elvehjem homogenizer or thelike thereby giving a uniform solution. A tissue homogenate may beprepared by adding a buffer cooled with ice to a tissue in an amount offrom 5 to 10 volume times the weight of the tissue, homogenizing itusing a Potter-Elvehjem homogenizer in ice thereby giving a uniformsolution, and then further ultrasonically homogenizing it for a fewseconds. The buffer may be Tris buffer (50 mM Tris-HCl (pH 8.0), 1 mMEDTA) or Hepes buffer (1 mM EDTA, 100 mM NaCl, 12.5 mM Hepes, pH 8.0).For example, the test methods of Example 438 and Example 439 areapplicable to the case. A lysate of E. coli transformed with anexpression vector that contains an FAAH or functional FAAH-encodingpolynucleotide may be prepared by collecting cells of E. coli throughcentrifugation and then dissolving them in a lysis buffer (for example,20 mM Tris-HCl (pH 8.0), 500 mM NaCl, 10% glycerol, 0.2 mM EDTA, 0.5 mMDTT, 10 mM imidazole, 1% n-octyl-β-D-glucopyranoside).

d) Purified Product of FAAH or Functional FAAH Purified from c):

A purified product of FAAH or functional FAAH may be prepared from a) acell or tissue expressing FAAH or functional FAAH or b) a lysate or ahomogenate of a transformant transformed with an expression vector thatcontains an FAAH or functional FAAH-encoding polynucleotide, accordingto an ordinary purification method of affinity chromatography,electrochromatography, gel filtration chromatography, ion-exchangechromatography or partition chromatography.

Concretely, the purification is as follows: A cell or tissue expressingFAAH or functional FAAH is homogenized in a solvent containing sucrose,and then subjected to centrifugation and ultra-high-speed centrifugationto obtain a microsome fraction, thereafter this is dissolved in asolvent containing Triton-X and further centrifuged for deposit removal,and the resulting protein-lysate is processed in a high-performanceprotein liquid chromatography (FPLC) system (by Pharmacia) (Ueda et al.,J. Biol. Chem., Vol. 270, pp. 23813-23827, 1995).

Alternatively, E. coli transformed so as to express a His tag-fused FAAHor functional FAAH is dissolved in a lysis buffer, then ultrasonicallyprocessed and centrifuged (e.g., at 10000×g for 20 minutes), and theresulting supernatant is mixed with a resin previously equilibrated withthe lysis buffer and having a high affinity with His tag, at a lowtemperature for at least 12 hours. Then, the resin is washed, and theHis tag-fused FAAH or functional FAAH is released from the resin toobtain its purified product.

For contacting a test substance with the above-mentioned cell or tissue,or the cell or tissue-lysate or homogenate prepared in the manner asabove, or the purified FAAH or functional FAAH product, employable is amethod of incubation for a predetermined period of time, with adding ornot adding a test substance to them. Concretely, a test substance isdissolved in a solution suitably selected depending on its solubilitytherein, such as distilled water or dimethyl sulfoxide (DMSO), and isadded to the above-mentioned cell or tissue, or the cell ortissue-lysate or homogenate, or the purified FAAH or functional FAAHproduct to be from 0.003 nM to 10 μM. The cell or tissue sample isincubated in a CO₂ incubator at 37° C. for 30 to 60 minutes; and theothers are at 4° C. to 37° C. for 30 to 90 minutes, thereby attainingthe intended contact with the test substance.

e) Tissue Homogenate or Blood of Test Animal Administered with TestSubstance:

When a test substance is administered to a test animal, then the testsubstance may be contacted with the FAAH or functional FAAH existing inthe tissue or the blood of the test animal. The test animal includes,for example, mammals such as mouse, rat, dog. A test substance may beadministered to the test animal as follows: A test substance issuspended or dissolved in a carrier generally used in accordance withthe property of the test substance, such as physiological saline water,dimethylformamide solution or 10% methyl cellulose solution, and it maybe administered to a test animal orally, subcutaneously,intraperitoneally or intravenously. After the administration, the tissueis taken out, and the tissue is homogenized according to the methoddescribed in the above c), thereby preparing a tissue homogenate.Concretely, for example, from 1 to 3 mg/kg of a test substance is orallyadministered to a 9-week age rat, and its brain, liver or monocyte takenout of it after 30 minutes is homogenized to prepare the tissuehomogenate Alternatively, from 0.3 to 3 mg/kg of a test substance isintravenously administered to a 13 to 18-month age dog, and its brain,liver or monocyte taken out of it after 30 minutes is homogenized toprepare the tissue homogenate. More concretely, for example, the tissuehomogenate may be prepared according to the method described in Example440. Blood may be collected from the heart or the descending aorta of atest animal to which the test substance has been administered.

(2) Step of Analyzing FAAH or Functional FAAH Activity Change:

For analyzing the FAAH or functional FAAH activity change, employable isa method of determining the change in the enzymatic activity of FAAH orfunctional FAAH based on the presence or absence of contact with a testsubstance. The enzymatic activity of FAAH or functional FAAH may bedetermined by contacting FAAH or functional FAAH with a substrate for apredetermined period of time, and measuring the amount of the decomposedproduct of the substrate. Alternatively, it may also be determined bymeasuring the amount of endocannabinoid that is an endogenous substratefor FAAH contained in a tissue or blood of a test animal.

For analyzing the test substance-dependent enzymatic activity change, asubstrate is contacted with FAAH or functional FAAH for a predeterminedperiod of time in the presence or absence of a test substance, and theratio of the amount of the decomposed product of the substrate in thepresence of the test substance to the amount of the decomposed productof the substrate in the absence of the test substance is obtained forthe intended analysis.

Alternatively, FAAH or functional FAAH previously contacted with a testsubstance, and FAAH or functional FAAH not contacted with a testsubstance are separately contacted with a substrate for a predeterminedperiod of time, and the ratio of the amount of the decomposed product ofthe substrate by the FAAH or functional FAAH previously contacted withthe test substance to the amount of the decomposed product of thesubstrate by the FAAH or functional FAAH not contacted with the testsubstance is obtained whereby the test substance-dependent enzymaticactivity change may be determined.

Further, the test substance-dependent enzymatic activity change may alsobe determined by measuring the amount of endocannabinoid in the tissueor blood of a test animal before and after administration of a testsubstance to the test animal, followed by obtaining the ratio of theendocannabinoid amount after the test substance administration to theendocannabinoid amount before the test substance administration; or bymeasuring the amount of endocannabinoid in the tissue or blood of a testanimal administered or not administered with a test substance, followedby obtaining the ratio of the endocannabinoid amount in the tissue orblood of the test animal administered with the test substance to theendocannabinoid amount in the tissue or blood of the test animal notadministered with the test substance, whereby the testsubstance-dependent enzymatic activity change may be determined.

FAAH and functional FAAH may be contacted with a substrate under thecondition mentioned below, in accordance with the condition of the FAAHor functional FAAH.

For contacting the FAAH or functional FAAH expressed in the cell ortissue of a) or b) in the above (1) with a substrate, there may beemployed a method of adding the substrate to the cultured cell or tissuein a buffer having a pH of from 7 to 9, and reacting them in a CO₂incubator at 37° C. or room temperature preferably for 30 to 60 minutes.The reaction may be stopped by transferring the cell or tissue onto iceto rapidly cool it, whereupon an FAAH inhibitor may be contacted with itat its sufficient concentration; or by adding a 1:1 (by volume) solutionof chloroform and methanol thereto. The cell or tissue is lysed orhomogenized according to the method described in the above (1) c),thereby producing a lysate or a homogenate thereof.

For contacting FAAH or functional FAAH in the lysate or homogenate of acell or tissue in c) or e) in the above (1), with a substrate, there maybe employed a method of adding the substrate to the lysate or homogenatethat has been diluted with a buffer having a pH of from 7 to 9 so as tohave a protein concentration of preferably from 10 to 100 μg/ml, andreacting them under a temperature condition of from 4° C. to 37° C. Thereaction time may be suitably defined depending on the condition such asthe amount of the enzyme added, the amount of the substrate added andthe reaction temperature. For example, when they are reacted at roomtemperature, the reaction time may be from 30 to 90 minutes.

For contacting the purified FAAH or functional FAAH in the above (1) d)with a substrate, there may be employed a method of adding the substrateto a lysate or a homogenate that has been diluted with a buffer having apH of from 7 to 9, and reacting them under a temperature condition offrom 4° C. to 37° C. The reaction time may be suitably defined dependingon the condition such as the amount of the enzyme added, the amount ofthe substrate added and the reaction temperature. For example, when theyare reacted at room temperature, the reaction time may be from 30 to 90minutes.

For measuring the amount of the decomposed product of a substrate, theunreacted substrate and the decomposed product in the enzyme reactionsolution are separated from each other, and the amount of the decomposedproduct may be measured. For separating the unreacted substrate from thedecomposed product, the water-solubility of the decomposed product,ethanolamine may be utilized. For example, a 1:1 (by volume) solution ofchloroform and methanol is added to the enzyme reaction solution in anamount of 2 times the reaction solution, followed by stirring, and thencentrifuged, whereby the decomposed product containing in the upperlayer, water/ethanol layer may be separated from the unreacted substratecontained in the lower layer, chloroform layer. Alternatively, thesystem may be mixed with a liquid scintillation cocktail agent of nowater absorbability whereby the fat-soluble unreacted radioactivesubstrate may be taken into the cocktail agent and the decomposedproduct may be thereby separated from the unreacted substrate. Stillalternatively, the unreacted substrate may be separated from thedecomposed product through thin-layer chromatography or high-performanceliquid chromatography.

In case where a ³H- or ¹⁴C-labeled substrate, or a mixture of a labeledsubstrate and an unlabeled substrate is used, the amount of thedecomposed product or the amount of the unreacted substrate may bemeasured with a liquid scintillation counter, or it may be recorded asan X-ray latent image on an imaging plate and may be measured with animage plate reader.

In case where an unlabeled substrate is used, the absorbance at 205 nmof the system may be monitored through high-performance liquidchromatography, and the amount of the decomposed product or the amountof the unreacted substrate may be thereby measured (Lang et al., Anal.Biochem., Vol. 238, pp. 40-45, 1996).

When the amount of the unreacted substrate is measured, then amount ofthe unreacted substrate may be subtracted from the amount of thesubstrate added before the reaction, and the amount of the decomposedproduct may be thereby obtained. Alternatively, the amount of thedecomposed product of the substrate measured in a buffer alone notcontaining FAAH or functional FAAH, as a control, may be subtracted fromthe amount of the decomposed product of the substrate with FAAH orfunctional FAAH, whereby the net amount of the decomposed product of thesubstrate with FAAH or functional FAAH may be obtained.

The amount of endocannabinoid in a tissue homogenate may be measured,for example, by homogenizing a sample tissue with a 2:1:1 (by volume)solution of chloroform, methanol and 50 mM Tris (pH 8.0), followed bymeasuring the amount of the endocannabinoid contained in the organiclayer (chloroform layer) through liquid chromatography/isotope dilutionmass spectrometry (Cravatt et al., Proc., Natl. Acad. Sci. USA, Vol. 98,pp. 9371-9376, 2001).

The amount of endocannabinoid in blood may be measured, for example, asfollows: Plasma is separated from a blood sample, and the protein in theplasma is removed through centrifugation along with the same amount ofacetone (−20° C.) added thereto. Acetone is evaporated by a nitrogen jetapplied to the system, and a 1:2 (by volume) solution of methanol andchloroform is added to it, and the amount of endocannabinoid containedin the organic layer (chloroform layer) is measured through liquidchromatography/isotope dilution mass spectrometry (Giuffraida et al.,Eur. J. Pharmacol., Vol. 408, pp. 161-168, 2000).

(3) Step of Selecting Substance that Inhibits the Activity of FAAH orFunctional FAAH:

A substance that inhibits the activity of FAAH or functional FAAH may beselected as follows: A test substance is contacted with FAAH orfunctional FAAH, this is compared with a case not contacted with thetest substance, and a substance that decreases the amount of thedecomposed product of the substrate may be selected.

Concretely, a test substance is contacted with FAAH or functional FAAH,and this is compared with a case not contacted with a test substance. Inthis, the substance with which the amount of the decomposed product ofthe enzyme decreases preferably to ½ or less may be screened for aremedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain.

Alternatively, a test substance having a different concentration iscontacted with FAAH or functional FAAH; and based on the amount of thedecomposed product of the substrate not contacted with the testsubstance, as 100%, the relative value (%) of the decomposed product ofthe substrate contacted with the test substance having a differentconcentration is obtained; or based on the amount of the decomposedproduct of the substrate not contacted with the test substance, as 100%,and based on the amount of the decomposed product of the substrate in acase where a known FAAH inhibitor having a sufficient concentration iscontacted with FAAH or functional FAAH for a sufficient period of time,as 0%, the relative value (%) of the amount of the decomposed product ofthe substrate contacted with the test substance having a differentconcentration is obtained. In an inhibition curve drawn on a graph inwhich the relative value (%) of the decomposed product of the substrateis on the vertical axis and the concentration of the test substance ison the horizontal axis, the concentration of the test substance thatgives a relative value, 50%, of the decomposed product of the substrate(IC₅₀ value) is computed; and the substance of which the IC₅₀ value ispreferably at most 1 μM, more preferably at most 100 nM is screened fora remedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain. For example, the tests ofExample 438 to Example 440 are referred to.

Still alternatively, a test substance is administered to a test animal,and the amount of endocannabinoid in the tissue or blood of the animalis compared with each other before and after the test substanceadministration; and the substance that increases the amount preferablyto 1.5 times may be selected for a substance that inhibits the activityof FAAH or functional FAAH, or that is, the substance may be screenedfor a remedy for urinary frequency and urinary incontinence, a remedyfor overactive bladder and/or a remedy for pain.

[2] Test Substance:

Not specifically defined, the test substance for use in the screeningmethod of the present invention includes, for example,commercially-available products (including peptides), various knowncompound registered in Chemical File (including peptides), compoundgroups obtained according to combinatorial chemistry technology (Terrettet al., J. Steele. Tetrahedron, Vol. 51, pp. 8135-8173, 1995),microorganisms-derived culture supernatants, plant or sea life-derivednatural components, animal tissue extracts, as well as compounds(including peptides) produced through chemical or biologicalmodification of the compounds (including peptides) selected according tothe screening method of the present invention.

[3] Pharmaceutical Composition for Treatment of Urinary Frequency andUrinary Incontinence, for Treatment of Overactive Bladder and/or forTreatment of Pain:

As the active ingredient of the pharmaceutical composition of thepresent invention, usable is a substance that inhibits the activity ofFAAH or functional FAAH, in which the inhibitor substance may beselected, for example, according to the screening method of the presentinvention.

The pharmaceutical composition of the present invention is not limitedto a pharmaceutical composition that contains, as the active ingredientthereof, the substance obtained according to the screening method of thepresent invention, but may include any and every pharmaceuticalcomposition for treatment of urinary frequency and urinary incontinence,for treatment of overactive bladder and/or for treatment of pain thatcontains, as the active ingredient thereof, a substance to inhibit theactivity of FAAH or functional FAAH; and preferably, this is apharmaceutical composition for treatment of urinary frequency andurinary incontinence, for treatment of overactive bladder and/or fortreatment of pain.

The effect for treatment of urinary frequency and urinary incontinence,the effect for treatment of overactive bladder and/or the effect fortreatment of pain may be confirmed in the manner as above.

The composition containing, as the active ingredient thereof, asubstance that inhibits the activity of FAAH or functional FAAH, forexample, DNA, protein (including antibody or antibody fragment), peptideor any other compound may be prepared as a pharmaceutical compositionusing pharmaceutically acceptable carrier, excipient and/or any otheradditive generally used in preparation of pharmaceutical compositions,depending on the type of the active ingredient therein.

The administration of the composition can be accompanied by, forexample, oral administration via tablets, pills, capsules, granules,fine granules, powders or oral liquids; or parenteral administration viainjections such as intravenous, intramuscular or intraarticularinjections, suppositories, endermic preparations or intramucosalpreparations. Especially for peptides that are digested in stomach,parenteral administration such as intravenous injection is preferred.

The solid composition for oral administration may comprise a mixture ofat least one or more active ingredients and at least one inert diluents,for example, lactose, mannitol, glucose, microcrystalline cellulose,hydroxypropyl cellulose, starch, polyvinylpyrrolidone or magnesiumaluminometasilicate. In addition to inert diluents, the solidcomposition may contain other additives, in an ordinary manner, forexample, lubricants, disintegrators, stabilizers, solubilizers orsolubilization assisting agents. The tablets and pills may be optionallycoated with sugar or with gastric or enteric coat film.

The liquid composition for oral administration includes, for example,emulsions, solutions, suspensions, syrups and elixirs, and may containordinary inert diluents, for example, purified water or ethanol. Inaddition to inert diluents, the liquid composition may also contain, forexample, moistening agents, suspending agents, sweeteners, aromatics orantiseptics.

Injections for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions or emulsions. The aqueous solutionsor suspensions may contain, for example, distilled water for injectionor physiological saline, as a diluent. The diluents for the non-aqueoussolutions or suspensions includes, for example, propylene glycol,polyethylene glycol, vegetable oil (e.g., olive oil), alcohols (e.g.,ethanol) or Polysorbate 80. Such compositions may further containmoistening agents, emulsifiers, dispersants, stabilizers, solubilizersor solubilization assisting agents, or antiseptics. Such compositionsmay be sterilized, for example, by filtration through a bacteriaretaining filter, or through addition of a germicide thereto, or throughirradiation. If desired, a germ-free solid composition may be prepared,and before use, it may be dissolved in germ-free water or in any othergerm-free medium for injection.

The dose of the composition may be suitably determined depending on theintensity of the activity of the active ingredient, or that is, thesubstance obtained according to the screening method of the presentinvention, and on the symptom, the age and the sex of the subject forits administration.

For example, in oral administration, the dose may be generally fromabout 0.1 to 100 mg/day, preferably from 0.1 to 50 mg/day to an adult(body weight of 60 kg). In parenteral administration, the injection dosemay be from 0.01 to 50 mg/day, preferably from 0.01 to 10 mg/day.

EXAMPLES

The present invention is described in more detail with reference to thefollowing Examples. The compounds of the present invention should not belimited to the compounds described in the following Examples. Productionmethods of starting compounds are shown in Reference Examples. Somecompounds of the present invention may also be starting compounds forothers; and for convenience sake, their production methods may be givenherein as Reference Examples. The chemical structural formulae and thephysicochemical properties of the compounds obtained in ReferenceExamples are shown in Tables 1 to 15. The chemical structural formulaeof the compounds obtained in Examples are shown in Table 16 to Table 34;and the physicochemical properties thereof are in Tables 35 to 63. Thestructures of other compounds of the present invention are shown inTables 65 to 73. These compounds may be readily produced according tothe above-mentioned production methods or the methods described in thefollowing Reference Examples and Examples, or according to methodsself-obvious to those skilled in the art, or according to modificationsof those methods.

When commercially-available kits are used, the written instructionsattached thereto may be referred to.

The abbreviations given in this descriptions are as follows:

Rex: Reference Example

Ex: Example

Str: structural formula

DAT: physicochemical properties

¹H-NMR δ(ppm), solvent: nuclear magnetic resonance spectrum

In the physicochemical data of the compounds of Examples;

DMSO: DMSO-d6

MS m/z: mass spectral data

Com: compound

NC: cyano

Ph: phenyl

Me: methyl

diMe: dimethyl

Et: ethyl

Pr: propyl

iPr: isopropyl

Bu: butyl

tBu: tert-butyl

iBu: isobutyl

Pen: pentyl

Hex: hexyl

Hep: heptyl

Oct: octyl

cPr: cyclopropyl

cPen: cyclopentyl

cHex: cyclohexyl

cHep: cycloheptyl

cOct: cyclooctyl

Ac: acetyl

Cl: chloro

diCl: dichloro

CN: cyano

F: fluoro

diF: difluoro

FPh fluorophenyl

NCPh: cyanophenyl

diFPh: difluorophenyl

O₂N: nitro

MeO: methoxy

diMeO: dimethoxy

Br: bromo

diBr: dibromo

BrPh: bromophenyl

F₃C: trifluoromethyl

AcO: acetoxy

MeOCO or COOMe: methoxycarbonyl

tBuOCO or COOtBu: tert-butoxycarbonyl

HO: hydroxy

HOPh: hydroxyphenyl

H₂N: amino

PhCONH: benzoylamino

EtCONH: ethylcarbonylamino

Me₂N: dimethylamino

Et₂N: diethylamino

BIP2: 2-biphenyl

BIP3: 3-biphenyl

BIP4: 4-biphenyl

BIP5: 5-biphenyl

BIP6: 6-biphenyl

Thiop2: thiophen-2-yl

Thiop3: thiophen-3-yl

Thiop4: thiophen-4-yl

Thiop5: thiophen-5-yl

PYRR1: pyrrolidin-1-yl

PYRR2: pyrrolidin-2-yl

PYRR3: pyrrolidin-3-yl

PYRR4: pyrrolidin-4-yl

PYRR5: pyrrolidin-5-yl

Py2: pyridin-2-yl

Py3: pyridin-3-yl

Py4: pyridin-4-yl

Py5: pyridin-5-yl

IM1: imidazol-1-yl

IM2: imidazol-2-yl

IM3: imidazol-3-yl

IM4: imidazol-4-yl

BenzIM1: benzimidazol-1-yl

BenzIM2: benzimidazol-2-yl

BenzIM3: benzimidazol-3-yl

BenzIM4: benzimidazol-4-yl

BenzIM5: benzimidazol-5-yl

BenzIM6: benzimidazol-6-yl

Pyrazi1: pyrazin-1-yl

Pyrazi2: pyrazin-2-yl

Pyrazi3: pyrazin-3-yl

Pyrazi4: pyrazin-4-yl

Pyrazi5: pyrazin-5-yl

Pyrazi6: pyrazin-6-yl

PIPE1: piperidin-1-yl

PIPE2: piperidin-2-yl

PIPE3: piperidin-3-yl

PIPE4: piperidin-4-yl

PIPE5: piperidin-5-yl

PIPE6: piperidin-6-yl

PIPERA: piperazine

PIPERA1: piperazin-1-yl

PIPERA2: piperazin-2-yl

PIPERA3: piperazin-3-yl

PIPERA4: piperazin-4-yl

PIPERA5: piperazin-5-yl

Pyrazo1: pyrazol-1-yl

Pyrazo2: pyrazol-2-yl

Pyrazo3: pyrazol-3-yl

Pyrazo4: pyrazol-4-yl

Pyrazo5: pyrazol-5-yl

Mo: morpholine

Mo2: morpholin-2-yl

Mo3: morpholin-3-yl

Mo4: morpholin-4-yl

Mo5: morpholin-5-yl

Azep: hexahydroazepine

Azep1: hexahydroazepin-1-yl

Azep2: hexyhydroazepin-2-yl

Azep3: hexyhydroazepin-3-yl

Azep4: hexyhydroazepin-4-yl

Thiaz2: thiazol-2-yl

Thiaz3: thiazol-3-yl

Thiaz4: thiazol-4-yl

Thiaz5: thiazol-5-yl

QUI1: quinolin-1-yl

QUI2: quinolin-2-yl

QUI3: quinolin-3-yl

QUI4: quinolin-4-yl

QUI5: quinolin-5-yl

QUI6: quinolin-6-yl

QUI7: quinolin-7-yl

QUI8: quinolin-8-yl

ISOQUI2: isoquinolin-2-yl

ISOQUI3: isoquinolin-3-yl

ISOQUI4: isoquinolin-4-yl

ISOQUI5: isoquinolin-5-yl

ISOQUI6: isoquinolin-6-yl

ISOQUI7: isoquinolin-7-yl

ISOQUI8: isoquinolin-8-yl

NAPH1: naphthalen-1-yl

NAPH2: naphthalen-2-yl

NAPH3: naphthalen-3-yl

NAPH4: naphthalen-4-yl

NAPH5: naphthalen-5-yl

TEA: triethylamine

Sal: addition salt

HCl: hydrochloride

oxal: oxalate

fum: fumarate

p-tol: p-toluenesulfonate

Reference Example 1

A THF (10 ml) solution containing phenol (471 mg) and diethylazodicarboxylate (2.83 g, 40% Tol solution) was dropwise added to a THF(15 ml) solution containing tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (1.57 g) andtriphenylphosphine (1.70 g), at 0° C., followed by stirring at roomtemperature for 24 hours. Water (40 ml) was added to the reactionsolution, followed by extraction with EtOAc. The organic layer waswashed with an aqueous 1 M sodium hydroxide solution and saturated brinein that order, and then dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent; hexane:EtOAc=4:1(v/v)) to obtain a colorless oil (1.14 g). The resulting compound wasdissolved in EtOAc, a 4 M hydrogen chloride/EtOAc solution (9.6 ml) wasadded thereto, followed by stirring at room temperature for 5 hours toobtain 4-(phenoxymethyl)piperidine hydrochloride (680 mg) as colorlesspowder.

In the same manner as in Reference Example 1, the compounds of ReferenceExamples 2 to 27 were obtained.

Reference Example 28

Water (10 ml), sodium carbonate (4.76 g) and tetrakistriphenylphosphinepalladium (866 mg) were added in that order to a dimethoxyethane (50 ml)solution containing 3-bromobenzamide (3.0 g) and(3-hydroxyphenyl)boronic acid (2.27 g), followed by stirring at 60° C.for 24 hours. The reaction solution was cooled, diluted with EtOAc, andthe organic layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: EtOAc) to obtain a pale yellow powder (2.74 g). Using theresulting compound and in the same manner as in Reference Example 1, thecompound of Reference Example 28 was obtained.

Reference Example 29

A THF (80 ml) solution containing 4-(benzyloxy)phenol (8.0 g) anddiethyl azodicarboxylate (26 ml, 40% Tol solution) was dropwise added toa THF (80 ml) solution containing tert-butyl4-hydroxypiperidine-1-carboxylate (12 g) and triphenylphosphine (16 g)at 0° C., followed by stirring at room temperature for 24 hours. Water(40 ml) was added to the reaction solution, followed by extraction withEtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxidesolution and saturated brine in that order, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane:EtOAc=8:1 (v/v)) to obtain a colorless oil (12.4 g).

10% palladium-carbon (catalytic amount) was added to an ethanol (100 ml)solution containing the resulting compound (5.18 g), followed bystirring in a hydrogen gas atmosphere at room temperature under normalpressure for 16 hours. The catalyst was removed by filtration, and theresulting filtrate was concentrated under reduced pressure to obtain apale brown solid (4.0 g).

1-(Bromomethyl)-3-fluorobenzene (2.5 ml) and potassium carbonate (2.8 g)were added to an acetonitrile (100 ml) solution containing the resultingcompound (4.0 g), followed by heating at 80° C. for 22 hours. The solidmatter was removed by filtration, the resulting filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) toobtain a colorless solid (5.15 g).

The resulting compound (5.15 g) was dissolved in EtOAc (20 ml), a 4 Mhydrogen chloride/EtOAc solution (20 ml) was added thereto, followed bystirring at room temperature for 5 hours. Then, the solvent wasevaporated under reduced pressure. The residue was dissolved in water,neutralized with an aqueous 1 M sodium hydroxide solution, and the solidformed was dried to obtain 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine(3.70 g).

In the same manner as in Reference Example 29, the compounds ofReference Examples 30 to 36 were obtained.

Reference Example 37

Diethyl azodicarboxylate (11 ml, 40% Tol solution) was dropwise added toa THF (30 ml) solution containing tert-butyl4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6.1 g)and 6-chloro-2-pyridinol (2.0 g) at 0° C., followed by stirring at roomtemperature for 24 hours. Water was added to the reaction solution,followed by extraction with EtOAc. The organic layer was washed with anaqueous 1 M sodium hydroxide solution, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).

(3-Fluorophenyl)methanol (220 mg) and potassium tert-butoxide (200 mg)were added to a DMF (5 ml) solution containing tert-butyl4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (500 mg), followedby heating at 100° C. for 30 minutes. Then, (3-fluorophenyl)methanol(220 mg) and potassium tert-butoxide (200 mg) were added thereto,followed by heating at 110° C. for 30 minutes. Water was added to thereaction solution, followed by extraction with EtOAc. The organic layerwas washed with an aqueous saturated sodium hydrogencarbonate solution,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain awhite solid (420 mg).

The resulting compound (400 mg) was dissolved in EtOAc (5 ml), a 4 Mhydrogen chloride/EtOAc solution (3 ml) was added thereto, followed bystirring overnight at room temperature. The precipitated solid wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 2-[(3-fluorobenzyl)oxy]-6-(4-piperidinoxy)pyridinehydrochloride (310 mg).

In the same manner as in Reference Example 37, the compound of ReferenceExample 38 was obtained.

Reference Example 39

Water (4 ml), sodium carbonate (610 mg) and tetrakistriphenylphosphinepalladium (110 mg) were added in that order to a Tol (10 ml) solutioncontaining tert-butyl4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (500 mg) and[3-(aminocarbonyl)phenyl]boronic acid (320 mg), followed by heatingovernight at 100° C. The reaction solution was cooled and diluted withEtOAc. The organic layer was washed with an aqueous solution ofanhydrous sodium hydrogencarbonate, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=1:2 (v/v)) to obtain a pale yellow powder (590 mg).

The resulting compound (590 mg) was dissolved in EtOAc (5 ml), and a 4 Mhydrogen chloride/EtOAc solution (5 ml) was added thereto, followed bystirring overnight at room temperature. The precipitated solid wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 3-[6-(4-piperidinyloxy)-2-pyridinyl]benzamidehydrochloride (440 mg).

Reference Example 40

TEA (4.6 ml) and methanesulfonyl chloride (2.0 ml) were dropwise addedto a methylene chloride (80 ml) solution containing tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate (5.0 g) at 0° C., followed bystirring at room temperature for 3 hours. An aqueous sodiumhydrogencarbonate solution and methanol were added to the reactionsolution, followed by stirring at room temperature for 30 minutes. Thiswas extracted with chloroform, and the organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: chloroform:methanol=10:1(v/v)) to obtain a colorless solid (6.1 g).

Sodium hydride (541 mg, 60% in oil) was added to a DMF (80 ml) solutioncontaining the resulting compound (2.0 g) and phenylpropanol (1.3 g) at0° C., followed by heating at 100° C. for 20 hours. The reactionsolution was cooled, water was added thereto, followed by extractionwith EtOAc. This was washed with an aqueous 1 M hydrochloric acidsolution, an aqueous saturated sodium hydrogencarbonate solution andsaturated brine in that order, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:chloroform:methanol=20:1 (v/v)) to obtain a yellow oil (1.96 g).

The resulting compound (1.96 g) was dissolved in EtOAc (5 ml), and a 4 Mhydrogen chloride/EtOAc solution (10 ml) was added thereto, followed bystirring at room temperature for 2 hours. The solid formed was collectedby filtration and dried to obtain 4-[2-(3-phenylpropoxy)ethyl]piperidinehydrochloride (1.55 g).

Reference Example 41

TEA (2.30 ml) and methanesulfonyl chloride (1.22 ml) were dropwise addedto a THF (40 ml) solution containing tert-butyl4-hydroxypiperidine-1-carboxylate (3.02 g) at 0° C., followed bystirring at room temperature for 1 hour. EtOAc (50 ml) and water (50 ml)were added to the reaction solution. The organic layer was washed withaqueous 5% citric acid solution, an aqueous saturated sodiumhydrogencarbonate solution and saturated brine in that order, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to obtain a pale orange oil. The resulting oil was dissolved inDMA (25 ml), and cesium carbonate (5.38 g) and 4-sulfanylphenol (1.89 g)were added thereto, followed by heating at 50° C. for 2 hours. Thereaction solution was cooled, water was added thereto, followed byextraction with EtOAc. The organic layer was washed with an aqueous 1 Mhydrochloric acid solution and saturated brine in that order, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain tert-butyl4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (3.40 g) ascolorless powder.

1-(Bromomethyl)-3-fluorobenzene (0.436 ml) and potassium carbonate (670mg) were added to an acetonitrile (15 ml) solution containing tert-butyl4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (1.00 g), followedby heating at 80° C. for 2 hours. The reaction solution was cooled,saturated brine was added thereto, followed by extraction withchloroform. The organic layer was dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=8:1 (v/v)) to obtain tert-butyl4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate(1.50 g) as colorless powder.

Tert-butyl4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (501mg) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAcsolution (3 ml) was added thereto, followed by stirring at roomtemperature for 3 hours. Then, the solvent was evaporated under reducedpressure. The residue was dissolved in water, neutralized with anaqueous 1 M sodium hydroxide solution, followed by extraction withchloroform. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure to obtain4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine (328 mg).

In the same manner as in Reference Example 41, the compound of ReferenceExample 42 was obtained.

Reference Example 43

mCPBA (1.64 g) was added to a chloroform (20 ml) solution containingtert-butyl4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate(1.50 g) obtained in the method of Reference Example 41, at 0° C.,followed by stirring at room temperature for 17 hours. The solid wasremoved by filtration, and an aqueous 10% sodium sulfate solution wasadded to the filtrate, followed by extraction with chloroform. Theorganic layer was washed with an aqueous saturated sodiumhydrogencarbonate solution, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=2:1(v/v)) to obtain a colorless powder (1.58 g). The resulting powder (1.56g) was dissolved in EtOAc (10 ml), a 4 M hydrogen chloride/EtOAcsolution (8 ml) was added thereto, followed by stirring at roomtemperature for 2 hours. Then, the solid was collected by filtration andwashed with EtOAc to obtain4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfonyl)piperidine hydrochloride(1.13 g) as colorless powder.

In the same manner as in Reference Example 43, the compounds ofReference Examples 44 to 46 were obtained.

Reference Example 47

A THF (5 ml) solution of tert-butyl4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (495 mg) obtainedin the method of Reference Example 41 and diethyl azodicarboxylate (1.04g, 40% Tol solution) were dropwise added to a THF (5 ml) solutioncontaining cyclohexylmethanol and triphenylphosphine (629 mg), at 0° C.,followed by stirring at room temperature for 24 hours. Water (40 ml) wasadded to the reaction solution, followed by extraction with EtOAc. Theorganic layer was washed with an aqueous 1 M sodium hydroxide solutionand saturated brine in that order, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=9:1 (v/v)) to obtain tert-butyl4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (744mg) as pale yellow oil.

The resulting tert-butyl4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (635mg) was dissolved in EtOAc (7 ml), and a 4 M hydrogen chloride/EtOAcsolution (3.6 ml) was added thereto, followed by stirring at roomtemperature for 6 hours. The solid was collected by filtration andwashed with EtOAc to obtain4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine hydrochloride (485mg) as colorless powder.

In the same manner as in Reference Example 47, the compound of ReferenceExample 48 was obtained.

Reference Example 49

Sodium hydride (355 mg, 60% in oil) and benzyl bromide (1.0 ml) wereadded to a THF (40 ml) solution containing tert-butyl4-hydroxypiperidine-1-carboxylate (1.5 g), followed by heating at 60° C.for 13 hours. The reaction solution was cooled, water was added thereto,followed by extraction with EtOAc. This was washed with an aqueous 1 Mhydrochloric acid solution, an aqueous saturated sodiumhydrogencarbonate solution and saturated brine in that order, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain a colorlessoil (1.91 g).

The resulting compound (1.8 g) was dissolved in EtOAc (5 ml), and a 4 Mhydrogen chloride/EtOAc solution (15 ml) was added thereto, followed bystirring at room temperature for 3 hours. The reaction solution wasdiluted with isopropyl ether, and the solid formed was collected byfiltration and dried to obtain 4-(benzyloxy)piperidine hydrochloride(1.32 g).

In the same manner as in Reference Example 49, the compounds ofReference Examples 50 to 53 were obtained.

Reference Example 54

Diethyl azodicarboxylate (2.6 ml, 40% Tol solution) was dropwise addedto a THF (10 ml) solution containing (3-fluorophenyl)methanol (730 mg),triphenylphosphine (1.5 g) and 6-chloro-3-pyridinol (500 mg) at 0° C.,followed by stirring at room temperature for 24 hours. The reactionsolution was diluted with EtOAc. The organic layer was washed with anaqueous saturated sodium hydrogencarbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain a white solid(810 mg).

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) and potassiumtert-butoxide (570 mg) were added to a DMF (10 ml) solution containingthe resulting white solid (800 mg), followed by heating at 130° C. for 1hour. Then, potassium tert-butoxide (400 mg) was added thereto, followedby further heating at 130° C. for 1 hour. The reaction solution wascooled to room temperature, diluted with EtOAc, washed with an aqueoussaturated sodium hydrogencarbonate solution, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane:EtOAc=7:1 (v/v)) to obtain a white solid (350 mg).

The resulting compound (345 mg) was dissolved in EtOAc (3 ml), and a 4 Mhydrogen chloride/EtOAc solution (2 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 6-[(3-fluorobenzyl)oxy]-2-(4-piperidinoxy)pyridinehydrochloride (260 mg).

Reference Example 55

[1-(Tert-butoxycarbonyl)piperidin-4-yl]acetic acid (0.60 g) wasdissolved in dimethylformamide (12 ml), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.89 g),1-hydroxybenzotriazole (0.50 g) and benzylamine (0.40 g) were addedthereto, followed by stirring at room temperature for 15 hours. Waterwas added to the reaction solution and stirred for 1 hour. Then, sodiumhydrogencarbonate solution was added thereto, followed by extractionwith EtOAc. The organic layer was washed with 0.5 M hydrochloric acidand saturated brine in that order. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorlesspowder (0.69 g).

The resulting compound (0.69 g) was dissolved in EtOAc (10 ml), and a 4M hydrogen chloride/EtOAc solution (2.2 ml) was added thereto, followedby stirring at room temperature for 20 hours. The reaction solution wasconcentrated into a dry solid to obtainN-benzyl-2-piperidin-4-ylacetamide hydrochloride (0.62 g).

Reference Example 56

Phosphoric acid (7 ml) and diphosphorus pentoxide (14 g) were heated at150° C. for 30 minutes, N-methylbenzene-1,2-diamine (1.3 g) and4-piperidin-4-ylbutanoic acid hydrochloride (1.5 g) were added thereto,followed by heating at 120° C. for 3 hours. The reaction solution waspoured into water, neutralized with aqueous sodium hydroxide solution,and then extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: chloroform:methanol:aqueous ammonia=10:1:0.1(v/v/v)) to obtain 1-methyl-2-(3-piperidin-4-ylpropyl)-1H-benzimidazole(1.61 g).

Reference Example 57 and Reference Example 58

Potassium tert-butoxide (1.72 g) was added to a THF (30 ml) solutioncontaining [4-(methoxycarbonyl)benzyl](triphenyl)phosphonium bromide(7.51 g) at 0° C., followed by stirring for 1 hour. A THF (20 ml)solution containing tert-butyl 4-formylpiperidine-1-carboxylate(Beilstein Registry No. 7704210, 2.96 g) was dropwise added to thereaction solution at 0° C., followed by stirring for 14 hours. Water wasadded to the reaction solution, followed by extraction with EtOAc. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe residue was purified by silica gel column chromatography (eluent:hexane:EtOAc 9:1 (v/v)) to obtain a yellow oil (3.77 g).

The resulting compound (3.75 g) was dissolved in methanol (20 ml) andTHF (10 ml), and an aqueous 1 M sodium hydroxide solution (16.3 ml) wasadded thereto, followed by stirring at 50° C. for 4 hours. The reactionsolution was cooled, and the solvent was evaporated under reducedpressure. This was made acidic with 1 M hydrochloric acid added, and thesolid precipitated was collected by filtration and washed with water toobtain a pale brown powder (2.82 g).

Ammonium chloride (2.26 g), 1-ethyl-3-(dimethylaminopropyl)carbodiimidehydrochloride (3.24 g), 1-hydroxybenzotriazole (1.14 g) and TEA (5.88ml) were added to a DMF (30 ml) solution containing the resultingcompound (2.80 g), followed by stirring at room temperature for 32hours. Water was added to the reaction solution, and the solidprecipitated was collected by filtration and washed with water to obtaina pale brown powder (2.61 g).

The resulting compound (2.58 g) was dissolved in EtOAc (15 ml), and a 4M hydrogen chloride/EtOAc solution (15 ml) was added thereto, followedby stirring at room temperature for 8 hours. The solid formed wascollected by filtration, washed with EtOAc, and dried to obtain4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (1.92 g) (ReferenceExample 57).

10% Palladium-carbon (catalytic amount) was added to a methanol (15ml)/water (5 ml) solution containing4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followedby stirring in a hydrogen gas atmosphere at room temperature undernormal pressure for 4 hours. The catalyst was removed by filtration, andthe resulting filtrate was concentrated under reduced pressure. Theresulting solid was recrystallized from ethanol/acetonitrile to obtain4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (ReferenceExample 58).

Reference Example 59

Sodium triacetoxyborohydride (2.2 g) was added to a dichloromethane (30ml) solution containing tert-butyl4-(4-aminophenoxy)-1-piperidinecarboxylate (2.0 g, Beilstein RegistryNo. 9262581), cyclohexenecarbaldehyde (770 mg) and acetic acid (1.25 g),at 0° C., followed by stirring at room temperature for 2 hours. Anaqueous saturated sodium hydrogencarbonate solution was added to thereaction solution, followed by extraction with chloroform. The organiclayer was washed with an aqueous saturated sodium hydrogencarbonatesolution, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the resulting solid wasrecrystallized from EtOAc/hexane to obtain a pale brown crystal (2.0 g).

Sodium triacetoxyborohydride (1.1 g) was added to a dichloromethane (20ml) solution containing the resulting crystal (970 mg), an aqueous 37%formaldehyde solution (0.94 ml) and acetic acid (0.75 g), at 0° C.,followed by stirring at room temperature for 2 hours. An aqueoussaturated sodium hydrogencarbonate solution was added to the reactionsolution, followed by extraction with chloroform. The organic layer waswashed with an aqueous saturated sodium hydrogencarbonate solution, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the resulting oil was dissolved in EtOAc (15 ml).A 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto,followed by stirring overnight at room temperature. The solidprecipitated was collected by filtration, washed with EtOAc, and driedunder reduced pressure to obtainN-(cyclohexylmethyl)-N-methyl-4-(4-piperidinyloxy)aniline hydrochloride(820 mg).

Reference Example 60

In an argon stream atmosphere, tris(dibenzylideneacetone)dipalladium (95mg) was added to a Tol (10 ml) solution containing benzyl 3-iodophenylether (1.1 g), tert-butyl 1-piperazinecarboxylate (640 mg), sodiumtert-butoxide (500 mg) and 2-biphenylyl(dicyclohexyl)phosphine (70 mg),followed by heating at 80° C. for 1 hour. The reaction solution wascooled, diluted with EtOAc, and the organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=5:1 (v/v)) toobtain a brown solid (950 mg).

The resulting solid (940 mg) was dissolved in EtOAc (5 ml), and a 4 Mhydrogen chloride/EtOAc solution (5 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 1-[3-(benzyloxy)phenyl]piperazine dihydrochloride(840 mg).

Reference Example 61

Diethyl azodicarboxylate (4.8 ml, 40% Tol solution) was dropwise addedto a THF (60 ml) solution containing 4-(benzyloxy)-2-chlorophenol (1.7g, Beilstein Registry No. 6582932), triphenylphosphine (2.8 g) andtert-butyl 4-hydroxypiperidine-1-carboxylate (2.1 g) at 0° C., followedby stirring at room temperature for 24 hours. The reaction solution wasdiluted with EtOAc. The organic layer was washed with aqueous saturatedsodium hydrogencarbonate solution, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=5:1 (v/v)) to obtain a white solid (2.3 g).

The resulting compound (1.0 g) was dissolved in EtOAc (10 ml), and a 4 Mhydrogen chloride/EtOAc solution (10 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 4-[4-(benzyloxy)-2-chlorophenoxy]piperidinehydrochloride (690 mg).

Reference Example 62

Thionyl chloride (10 ml) was dropwise added to a DMF (5 ml) solution ofsodium 4-hydroxybenzenesulfonate (1.00 g), followed by heating at 65° C.for 3 hours. The reaction solution was cooled and Tol (10 ml) was addedthereto. The solvent was evaporated under reduced pressure, water wasadded, followed by extraction with chloroform. The organic layer waswashed with aqueous saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to obtain acolorless solid (587 mg).

At 0° C., an acetonitrile (10 ml) solution of the previously-obtainedcompound (579 mg) was added to an acetonitrile (10 ml) solutioncontaining 1-tert-butoxycarbonylpiperazine (672 mg) and pyridine (0.58ml), followed by stirring at room temperature for 2 hours. The solventwas evaporated under reduced pressure, Tol (10 ml) was added thereto andazeotroped. Then, water was added, followed by extraction with EtOAc.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to obtain a colorless solid (0.41 g).

Potassium carbonate (248 mg) was added to an acetonitrile (20 ml)solution containing the resulting compound (0.41 g) and1-(bromomethyl)-3-fluorobenzene (340 mg), followed by heating at 80° C.for 3 hours. The solid was removed through filtration, the resultingfiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=5:1(v/v)) to obtain a colorless solid (469 mg).

The resulting compound (460 mg) was dissolved in a mixed solution ofEtOAc (5 ml) and THF (5 ml), and 4 M hydrogen chloride/EtOAc solution(20 ml) was added thereto, followed by stirring at 70° C. for 3 hours.Then, the solvent was evaporated under reduced pressure. The residue wasdissolved in water, neutralized with an aqueous 1 M sodium hydroxidesolution, and the solid formed was dried to obtain4-{4-[(3-fluorobenzyl)oxy]benzenesulfonyl}piperazine (304 mg).

Reference Example 63

Diethyl azodicarboxylate (3.3 ml, 40% Tol solution) was dropwise addedto a THF (30 ml) solution containing 4-(benzyloxy)-3-chlorophenol (1.2g, Beilstein Registry No. 5527577), triphenylphosphine (1.9 g) andtert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g) at 0° C., followedby stirring at room temperature for 24 hours. The reaction solution wasdiluted with EtOAc, and the organic layer was washed with an aqueoussaturated sodium hydrogencarbonate solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane:EtOAc=5:1 (v/v)) to obtain a white solid (1.7 g).

The resulting compound (1.6 g) was dissolved in EtOAc (20 ml), and a 4 Mhydrogen chloride/EtOAc solution (15 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain 4-[4-(benzyloxy)-3-chlorophenoxy]piperidinehydrochloride (1.3 g).

Reference Example 64

3-Fluorobenzenesulfonyl chloride (3.2 g) was added to a pyridine (30 ml)solution containing tert-butyl4-(4-aminophenoxy)-1-piperidinecarboxylate (4.0 g, Beilstein RegistryNo. 9262581) at 0° C., followed by stirring overnight at roomtemperature. The solvent was evaporated under reduced pressure, anddiluted with chloroform. The organic layer was washed with an aqueous10% citric acid solution, water and saturated brine in that order, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=60:1 (v/v)) to obtain awhite solid (5.3 g).

Potassium carbonate (280 mg) and methyl iodide (0.28 ml) were added toan acetonitrile (10 ml) solution containing the resulting compound (700mg), followed by stirring at 50° C. for 3 hours. The reaction solutionwas diluted with EtOAc, the organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=3:1 (v/v)) toobtain a colorless oil (700 mg).

The resulting oil (700 mg) was dissolved in EtOAc (10 ml), and a 4 Mhydrogen chloride/EtOAc solution (5 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc, and dried under reducedpressure to obtain3-fluoro-N-methyl-N-[4-(4-piperidinyloxy)phenyl]benzenesulfonamidehydrochloride (480 mg).

Reference Example 65

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (630 mg) and1-hydroxybenzotriazole (440 mg) were added to a DMF (10 ml) solutioncontaining1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperidinecarboxylicacid (1.0 g), followed by stirring at room temperature for 1 hour. Then,an aqueous concentrated ammonia (2 ml) was added thereto, followed bystirring at room temperature for 3 hours. Water was added to thereaction solution, and the solid precipitated was collected byfiltration, washed with water and dried under reduced pressure to obtaina colorless solid (870 mg).

The resulting solid (860 mg) was dissolved in EtOAc (10 ml), and a 4 Mhydrogen chloride/EtOAc solution (5 ml) was added thereto, followed bystirring overnight at room temperature. The precipitated solid wascollected by filtration, washed with EtOAc and dried under reducedpressure to obtain benzyl 2-(aminocarbonyl)-1-piperazinecarboxylatehydrochloride (700 mg).

Reference Example 66

Pyridine (1.62 ml) and 4-nitrophenyl chlorocarbonate (2.22 g) were addedto an acetonitrile (20 ml) solution containing methyl4-(hydroxymethyl)benzoate at 0° C., followed by stirring at roomtemperature for 2 hours. An aqueous 5% citric acid solution was added tothe reaction solution, followed by extraction with EtOAc. The organiclayer was washed with an aqueous saturated hydrogencarbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=4:1(v/v)) to obtain a pale brown powder (2.39 g).

Tert-butyl piperazine-1-carboxylate (1.47 g) was added to anacetonitrile (30 ml) solution containing the resulting compound (2.37g), followed by stirring at room temperature for 8 hours. The reactionsolution was diluted with EtOAc and washed with an aqueous 0.5 M sodiumhydroxide solution. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: hexane:EtOAc=2:1 (v/v)) to obtain acolorless solid (3.32 g).

Methanol (0.34 ml) and an aqueous 1 M sodium hydroxide solution (8.52ml) were added to a THF (30 ml) solution containing the resultingcompound (3.30 g), followed by stirring at room temperature for 26hours. The solvent was evaporated under reduced pressure, an aqueous 1 Mhydrochloric acid solution was added to the residue, followed byextraction with chloroform. The organic layer was washed with saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue wasrecrystallized from hexane/EtOAc to obtain a colorless powder (2.37 g).

Ammonium chloride (321 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimidehydrochloride (767 mg), 1-hydroxybenzotriazole (270 mg) and TEA (0.83ml) were added to a DMF (10 ml) solution containing the resultingcompound (729 mg), followed by stirring at room temperature for 3 hours.Water was added to the reaction solution, and the solid precipitated wascollected by filtration, and washed with water to obtain a pale brownpowder (722 mg).

The resulting compound (700 mg) was dissolved in EtOAc (6 ml), a 4 Mhydrogen chloride/EtOAc solution (4.8 ml) was added thereto, followed bystirring at room temperature for 3 hours. The solid formed was collectedby filtration, washed with EtOAc, and dried to obtain4-(aminocarbonyl)benzyl piperazine-1-carboxylate hydrochloride (541 mg).

Reference Example 67

A THF (5 ml) solution containing methyl 4-hydroxybenzoate (460 mg) anddiethyl azodicarboxylate (0.71 ml) was dropwise added to a THF (5 ml)solution containing cyclohexylmethanol (510 mg) and triphenylphosphine(1.18 g) at 0° C., followed by stirring at room temperature for 24hours. An aqueous 1 M sodium hydroxide solution (40 ml) was added to thereaction solution, followed by extraction with EtOAc The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=4:1(v/v)) to obtain a colorless solid (930 mg).

An aqueous 1 M sodium hydroxide solution (4.4 ml) was added to amethanol (5 ml)/THF (3 ml) solution containing the resulting compound(920 mg), followed by stirring at 50° C. for 6 hours. This was cooled toroom temperature, and EtOAc (40 ml) and water (30 ml) were addedthereto, followed by stirring. The organic layer was extracted with anaqueous 1 M sodium hydroxide solution. The aqueous layers were combinedand made to have a pH of 1 with concentrated hydrochloric acid. Then,the aqueous layer was extracted with chloroform, and then dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was recrystallized from hexane/EtOAc to obtain4-(cyclohexylmethoxy)benzoic acid (600 mg).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (359 mg) and1-hydroxybenzotriazole (254 mg) were added to a DMF (10 ml) solutioncontaining the resulting compound (370 mg) and tert-butyl1-piperazinecarboxylate (350 mg), followed by stirring at roomtemperature for 12 hours. Water was added to the reaction solution, andthe solid precipitated was collected by filtration, washed with waterand dried under reduced pressure to obtain a colorless solid (610 mg).

The resulting compound (600 mg) was dissolved in EtOAc (6 ml), and a 4 Mhydrogen chloride/EtOAc solution (4 ml) was added thereto, followed bystirring overnight at room temperature. The solid precipitated wascollected by filtration, washed with EtOAc and dried under reducedpressure to obtain 1-[4-(cyclohexylmethoxy)benzoyl]piperazinehydrochloride (580 mg).

In the same manner as in Reference Example 67, the compounds ofReference Examples 68 to 72 were obtained.

Reference Example 73

At −70° C., a 1.59 M normal-butyllithium/THF solution (14.6 ml) wasadded to s 2 M dimethylamine/THF solution (11.6 ml), followed bystirring for 10 minutes. This was warmed to 0° C., and3-chloro-5-hydroxypyridine (1.00 g) was added thereto, followed bystirring overnight at room temperature. Ethanol (15 ml) was added, andthe solvent was evaporated under reduced pressure. Water was added tothe residue, followed by extraction with chloroform. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:chloroform:methanol=10:1 (v/v)) to obtain3-dimethylamino-5-hydroxypyridine (176 mg).

Reference Example 74

Tris-dibenzylideneacetone palladium (21 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (124 mg) and sodiumtert-butoxide (160 mg) were added in that order to a Tol (10 ml)solution containing 3-benzyloxy-5-bromopyridine (400 mg) and morpholine(158 mg), followed by heating at 85° C. for 4 hours. The solvent wasevaporated under reduced pressure, and the residue was purified throughsilica gel column chromatography (eluent: chloroform:methanol=20:1(v/v)) to obtain a colorless oil (372 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml)solution containing the resulting compound (370 mg), and in a hydrogengas atmosphere, this was stirred at room temperature and under normalpressure for 1.5 hours. The catalyst was removed by filtration, and theresulting filtrate was concentrated under reduced pressure to obtain5-hydroxy-3-morpholinylpyridine (248 mg).

In the same manner as in Reference Example 74, the compounds ofReference Examples 75 and 76 were obtained.

Reference Example 77

Sodium methoxide (393 mg) was added to a methanol (20 ml) solutioncontaining 5-(benzenesulfonyloxy)-2-(bromomethyl)pyridine (BeilsteinRegistry No. 7430370, 800 mg), followed by stirring at room temperaturefor 4 hours. Water was added to the reaction solution, followed byextraction with EtOAc. The organic layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: EtOAc) to obtain6-(methoxymethyl)pyridin-3-ol (200 mg).

Reference Example 78

TEA (0.21 ml) and di-tert-butyl dicarbonate (463 mg) were added in thatorder to a THF (10 ml) solution of 3-benzyloxy-5-aminopyridine (250 mg),followed by heating at 60° C. for 3 h ours. The solvent was evaporatedunder reduced pressure, water was added thereto, followed by extractionwith EtOAc. The organic layer was washed with an aqueous saturatedsodium hydrogencarbonate solution and saturated brine, and then driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorlesssolid (153 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml)solution containing the resulting compound (240 mg), and in a hydrogengas atmosphere, this was stirred at room temperature under normalpressure for 1.5 hours. The catalyst was removed by filtration, and theresulting filtrate was concentrated under reduced pressure to obtaintert-butyl (5-hydroxypyridin-3-yl)carbamate (167 mg).

Reference Example 79

At 0° C., a THF (10 ml) suspension of sodium hydride (60% oil mixture,139 mg) was added to a THF (10 ml) solution of methyldiethylphosphonoacetate (732 mg), followed by stirring for 15 minutes.Then, 5-(benzyloxy)nicotinaldehyde (495 mg) was added, followed bystirring at room temperature for 4 hours. Water was added to thereaction solution, followed by extraction with EtOAc. The organic layerwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to obtain acolorless solid (680 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml)solution containing the resulting compound (330 mg), and in a hydrogengas atmosphere, this was stirred at room temperature under normalpressure for 2 hours. The catalyst was removed by filtration, and theresulting filtrate was concentrated under reduced pressure to obtainmethyl 3-(5-hydroxypyridin-3-yl)propanoate (150 mg).

Reference Example 80

At −78° C., a THF (30 ml) solution of methyl 5-(benzyloxy)nicotinate(3.52 g) was added to a THF (100 ml) suspension of lithium aluminiumhydride (1.49 g), followed by stirring for 15 minutes and then stirringat room temperature for 2 hours. The reaction solution was cooled to 0°C., and then water (1.49 ml), an aqueous 15% sodium hydroxide solution(1.49 ml) and water (4.47 ml) were added thereto in that order. Thesolid was removed by filtration, and the resulting filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) toobtain a colorless solid (1.41 g).

Tert-butyl bromoacetate (609 mg), tetrabutylammonium hydrogensulfate (35mg) and an aqueous 50% sodium hydroxide solution (2 ml) were added inthat order to a benzene (20 ml) solution containing the resultingcompound (450 mg), followed by stirring overnight at room temperature.This was neutralized with an aqueous 1 M hydrochloric acid, followed byextraction with EtOAc. The organic layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=6:4 (v/v)) toobtain a colorless oil (576 mg).

10% palladium-carbon (catalytic amount) was added to an ethanol (20 ml)solution containing the resulting compound (570 mg), and in a hydrogengas atmosphere, this was stirred at room temperature under normalpressure for 1 hour. The catalyst was removed by filtration, and theresulting filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:chloroform:methanol=15:1 (v/v)) to obtaintert-butyl[(5-hydroxypyridin-3-yl)methoxy]acetate (400 mg).

Reference Example 81

Pentamethylbenzene (826 mg) was added to a TFA (10 ml) solutioncontaining methyl (2E)-3-[5-(benzyloxy)pyridin-3-yl]acrylate (300 mg),followed by stirring overnight at 60° C. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtaintert-butyl (5-hydroxypyridin-3-yl)acetate (180 mg).

Reference Example 82

Diisopropylethylamine (2.05 ml) and methoxymethyl chloride (0.89 ml)were added in that order to a THF (60 ml) solution of methyl3-hydroxynicotinate (1.50 g), and then stirred overnight at roomtemperature. The solvent was evaporated under reduced pressure, waterwas added thereto, followed by extraction with chloroform. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to obtain acolorless oil (2.01 g).

At −78° C., a THF (20 ml) solution of the resulting compound (1.98 g)was added to a THF (50 ml) suspension of lithium aluminium hydride (838mg), followed by stirring for 30 minutes and then stirring at roomtemperature for 2 hours. The reaction solution was cooled to 0° C., andwater (0.84 ml), an aqueous 15% sodium hydroxide solution (0.84 ml) andwater (2.52 ml) were added thereto in that order. The solid was removedby filtration, and the resulting filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: EtOAc) to obtain a colorless oil (838 mg).

Acetic anhydride (1.39 ml) was added to a pyridine (10 ml) solutioncontaining the resulting compound (828 mg), followed by stirring at roomtemperature for 1.5 hours. The solvent was evaporated under reducedpressure, Tol (10 ml) was added thereto and azeotroped to obtain acolorless oil (1.01 g).

4 M hydrogen chloride/dioxane solution (3.58 ml) was added to a dioxane(10 ml) solution of the resulting compound (1.01 g), followed bystirring at room temperature for 1 hour. The solvent was evaporatedunder reduced pressure to obtain (5-hydroxypyridin-3-yl)methyl acetatehydrochloride (973 mg).

Reference Example 95

Triphenylphosphine (2.8 g) was added to a Tol (50 ml) solution of3-cyanobenzyl bromide (2.0 g), followed by stirring at 80° C. for 5hours. This was cooled to room temperature, and the precipitated solidwas collected by filtration, and washed with Tol. This was dried underreduced pressure to obtain (3-cyanobenzyl)(triphenyl)phosphonium bromide(3.4 g).

Under ice cooling, sodium hydride (60% oil, 141 mg) was added to a DMF(20 ml) solution of (3-cyanobenzyl)(triphenyl)phosphonium bromide (1.6g) and tert-butyl 4-formyl-1-piperidinecarboxylate (0.75 g), followed bystirring overnight at room temperature. The reaction liquid was dilutedwith EtOAc, washed with water, and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the resulting residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=6:1(v/v)) to obtain an oil. 10% Palladium-carbon (100 mg) was added to anEtOAc (30 ml) solution of the resulting oil, followed by stirring in ahydrogen stream atmosphere for 2 hours. The catalyst was removed withCelite, and the solvent was concentrated to obtain an oil. The resultingoil was dissolved in EtOAc (10 ml), and 4 M hydrogen chloride/EtOAcsolution (5 ml) was added thereto, then stirred at room temperature for6 hours, and then concentrated. The resulting solid was washed withether and dried under reduced pressure to obtain3-[2-(4-piperidinyl)ethyl]benzonitrile hydrochloride (506 mg).

In the same manner as in Reference Example 95, the compounds ofReference Examples 96 to 101 were obtained.

Reference Example 102

Triphenylphosphine (85.8 g) was added to a Tol (400 ml) solution ofmethyl 3-bromomethylbenzoate (50.0 g), followed by stirring at 80° C.for 10 hours. After this was cooled to room temperature, the crystalprecipitated was collected by filtration and washed with Tol. This wasdried under reduced pressure to obtain(3-methoxycarbonylbenzyl)(triphenyl)phosphonium bromide (107.6 g).

Under ice cooling, potassium tert-butoxide (22.5 g) was added to a DMF(250 ml) solution of (3-methoxycarbonylbenzyl)(triphenyl)phosphoniumbromide (84.6 g), followed by stirring at room temperature for 30minutes. Then, a DMF (50 ml) solution of tert-butyl4-formyl-1-piperidinecarboxylate (30.6 g) was added to it under icecooling, and then stirred overnight at room temperature. Acetic acid(11.5 ml) was added to the reaction liquid, followed by stirring at roomtemperature for 1 hour. Then, this was diluted with EtOAc, washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the resulting residuewas purified by silica gel column chromatography (eluent:hexane:EtOAc=7:1 (v/v)). The residue was dissolved in EtOAc, activatedcharcoal was added thereto, followed by stirring at room temperature for2 hours. Activated charcoal was removed with Celite, and the solvent wasevaporated under reduced pressure to obtain a colorless oil.

10% Palladium-carbon (4.58 g) was added to an EtOAc (400 ml) solution ofthe resulting oil, followed by stirring in a hydrogen stream atmospherefor 2 hours. The catalyst was removed with Celite, and the solvent wasconcentrated to obtain tert-butyl4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g).

In the same manner as in Reference Example 102, the compound ofReference Example 103 was obtained.

Reference Example 104

Aqueous 1 M sodium hydroxide solution (196 ml) was added to a THF (200ml)/methanol (50 ml) mixed solution of tert-butyl4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g),followed by stirring at 60° C. for 2 hours. The organic solvent wasevaporated under reduced pressure, and under ice cooling, 0.5 Mhydrochloric acid (400 ml) was added to the residue. The reaction liquidwas diluted with EtOAc, washed with water and saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated to obtain3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (43.5 g)was obtained.

In the same manner as in Reference Example 104, the compound ofReference Example 105 was obtained.

Reference Example 106

3-{2-[1-(Tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (17.8 g)was dissolved in DMF (200 ml), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (15.4 g)and 1-hydroxybenzotriazole (10.8 g) were added thereto, followed bystirring at room temperature for 2 hours. Ammonium chloride (8.57 g) andTEA (22.3 ml) were added to the reaction liquid, followed by stirringovernight at room temperature. An aqueous saturated sodiumhydrogencarbonate solution was added to the reaction liquid, and theprecipitated crystal was collected by filtration and dried to obtaintert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate(10.8 g).

In the same manner as in Reference Example 106, the compounds ofReference Examples 107 to 118 were obtained.

Reference Example 119

Tert-butyl4-[2-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate(280 mg), carbon tetrabromide (247 mg) and 2,6-lutidine (103 μl) weredissolved in dichloromethane (5.6 ml), and under ice cooling,triphenylphosphine (195 mg) was added thereto, followed by stirring atroom temperature for 3 hours. The solvent was evaporated, and theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=3:7 (v/v)) to obtain tert-butyl4-{2-[4-(1-aziridinylcarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (136mg) as a colorless oil.

Reference Example 120

Tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate(13.8 g) was dissolved in EtOAc (200 ml), and 4 M hydrogenchloride/EtOAc solution (130 ml) was added thereto, followed by stirringat room temperature for 4 hours, and then concentrated. Acetonitrile wasadded to the resulting residue, followed by heating, and theprecipitated crystal was collected by filtration, washed with EtOAc, anddried under reduced pressure to obtain3-[2-(4-piperidinyl)ethyl]benzamide hydrochloride (11.2 g).

In the same manner as in Reference Example 120, the compounds ofReference Examples 121 to 139 were obtained.

Reference Example 140

In an argon stream atmosphere, sodium carbonate (0.43 g) andtetrakis(triphenylphosphine)palladium (80 mg) were added to a Tol (6ml)/water (2 ml) solution of tert-butyl4-[2-(3-bromophenyl)ethyl]-1-piperidinecarboxylate (0.50 g) andphenylboronic acid (0.20 g), followed by heating with stirring at 100°C. for 7 hours. This was cooled to room temperature, diluted with EtOAc,and washed with aqueous saturated sodium hydrogencarbonate solution.This was dried over anhydrous magnesium sulfate, then the solvent wasevaporated, and the resulting residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate (0.41 g).

4 M hydrogen chloride/EtOAc (1.5 ml) was added to an EtOAc (4 ml)solution of tert-butyl 4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate(0.41 g), followed by stirring overnight at room temperature. Theprecipitated crystal was collected by filtration, washed withEtOAc/hexane and dried under reduced pressure to obtain4-[2-(3-biphenyl)ethyl]piperidine hydrochloride (0.31 g).

In the same manner as in Reference Example 140, the compounds ofReference Examples 141 and 142 were obtained.

Reference Example 143

Under ice cooling, di-tert-butyl dicarbonate (2.6 g) was added to adichloromethane (50 ml) solution of 4,4′-(1,3-propane-diyl)dipiperidine(5.0 g), followed by stirring overnight at room temperature. Thereaction liquid was diluted with chloroform, washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the resulting residue was purified by silica gel columnchromatography (eluent: chloroform:methanol:aqueous concentratedammonia=4:1:0.1 (v/v)) to obtain tert-butyl4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (2.2 g).

In an argon atmosphere, sodium tert-butoxide, (0.52 g),tris(dibenzylideneacetone)dipalladium (100 mg) and2-(dicyclohexylphosphino)biphenyl (76 mg) were added to a Tol (22 ml)solution of 2-chloro-6-methylpyridine (0.56 g) and tert-butyl4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (1.1 g), followed byheating with stirring at 100° C. for 1 hour. This was cooled to roomtemperature, diluted with EtOAc, and washed with aqueous saturatedsodium hydrogencarbonate solution. This was dried over anhydrousmagnesium sulfate, the solvent was evaporated, and the resulting residuewas purified by silica gel column chromatography (eluent:hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidyl]propyl}-1-piperidinecarboxylate(1.3 g).

4 M hydrogen chloride/EtOAc (10 ml) was added to an EtOAc (25 ml)solution of tert-butyl4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidinyl]propyl}-1-piperidinecarboxylate(1.3 g), followed by stirring overnight at room temperature. Thereaction liquid was concentrated, then 2-propanol/diethyl ether wasadded thereto, followed by stirring. The precipitated solid wascollected by filtration, and dried under reduced pressure to obtain2-methyl-6-{4-[3-(4-piperidinyl)propyl]-1-piperidyl}pyridinedihydrochloride (1.1 g).

In the same manner as in Reference Example 143, the compounds ofReference Examples 144 and 145 were obtained.

Reference Example 146

Methanesulfonyl chloride (2.7 ml) was dropwise added to a methylenechloride (200 ml) solution of tert-butyl4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) at0° C., followed by stirring overnight at room temperature. The reactionliquid was washed with aqueous saturated sodium hydrogencarbonatesolution and saturated brine, then dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v)) toobtain tert-butyl4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g).

A DMI (20 ml) suspension of tert-butyl4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (1.00 g),1-piperazin-1-yl-isoquinoline dihydrochloride (980 mg), cesium carbonate(1.02 g) and sodium iodide (467 mg) was stirred at 140° C. for 1 hour.EtOAc was added to the reaction liquid, washed with water and aqueoussaturated sodium hydrogencarbonate solution in that order, then driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=1:1 (v/v)) to obtain tert-butyl4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate(1.07 g) as a pale yellow oil.

4 M hydrogen chloride/EtOAc solution (5.0 ml) was dropwise added to anEtOAc (15 ml) solution of tert-butyl4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate(1.44 g), followed by stirring overnight. The solvent was evaporated,the solid was washed with EtOAc and collected by filtration to obtain1-[4-(3-piperidin-4-ylpropyl)piperazin-1-yl]isoquinoline dihydrochloride(1.32 g) as a white solid.

In the same manner as in Reference Example 146, the compound ofReference Example 154 was obtained.

Reference Example 147

4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100ml) solution of methyl 5-hydroxynicotinate (5.3 g) anddiisopropylethylamine (6.1 ml), followed by stirring at room temperaturefor 1 hour. The reaction liquid was washed with water, and dried overanhydrous magnesium sulfate. The solvent was evaporated, and theresulting solid was washed with EtOAc/hexane and dried under reducedpressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate(8.4 g).

In the same manner as in Reference Example 147, the compound ofReference Example 148 was obtained.

Reference Example 151

A DMF (15 ml) solution of3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]benzoic acid (1.25 g),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (863 mg)and 1-hydroxybenzotriazole (608 mg) was stirred at room temperature for1 hour, and then a TEA (1.6 ml) solution of 2-bromoethylaminehydrobromide (2.30 g) was added thereto, followed by stirring overnight.Aqueous saturated sodium hydrogencarbonate solution was added to thereaction liquid, followed by extraction with EtOAc, then washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated to obtain a crude product of tert-butyl4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate.

4 M hydrogen chloride/EtOAc solution (5 ml) was added to an EtOAc (15ml) solution of the crude tert-butyl4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylateat room temperature, followed by stirring overnight. The solvent wasevaporated under reduced pressure to obtainN-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.27g) as a white solid.

TEA (0.90 ml) was dropwise added to an acetonitrile (30 ml) suspensionof N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride(1.20 g) and methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (1.02g), followed by stirring overnight at room temperature. The reactionsolvent was evaporated under reduced pressure, then aqueous saturatedsodium hydrogencarbonate solution was added thereto, extracted withEtOAc, and dried over anhydrous magnesium sulfate. This was filtered,the solvent was evaporated, and the residue was purified two timesthrough silica gel column chromatography (basic silica with eluent:hexane:EtOAc=1:2 (v/v), next neutral silica with eluent:chloroform:methanol=19:1 (v/v)) to obtain methyl5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate(762 mg) as a white powder.

A DMF (10 ml) suspension of methyl5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate(750 mg), potassium carbonate (300 mg) and potassium iodide (361 mg) wasstirred at 80° C. for 1 hour. The reaction liquid was left cooled, thenEtOAc was added thereto, washed with aqueous saturated sodiumhydrogencarbonate solution and saturated brine in that order, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain methyl5-{[(4-{2-[3-(aziridin-1-ylcarbonyl)phenyl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate(630 mg) as a colorless oil.

Reference Example 152

Under ice cooling, diphenylphosphorylazide (540 mg) was added to a Tolsolution (10 ml) of3-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl]benzoic acid (600 mg)and TEA (0.3 ml), followed by stirring at room temperature for 2 hours.EtOAc was added to the reaction solution, washed with aqueous saturatedsodium hydrogencarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to obtain a colorless oil (630 mg). A Tol solution (10 ml) ofthe resulting oil (400 mg) was stirred at 110° C. for 1 hour. This wascooled to room temperature, and aqueous 30% ammonia solution (0.2 ml)was added thereto, followed by stirring at room temperature for 15hours. EtOAc was added to the reaction solution, then washed withaqueous 1 N hydrochloric acid solution and saturated brine in thatorder, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent:chloroform:methanol=95:5 (v/v)) to obtain tert-butyl4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227mg).

4 M hydrogen chloride/EtOAc (4 ml) was added to an EtOAc (9 ml) solutionof tert-butyl4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227mg), followed by stirring at room temperature for 3 hours. The solventwas evaporated under reduced pressure to obtain1-{3-[2-(4-piperidyl)ethyl]phenyl}urea hydrochloride (185 mg).

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added toan acetonitrile (5 ml) solution of1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea hydrochloride (185 mg) and TEA(0.2 ml), followed by stirring overnight at room temperature. Thereaction liquid was diluted with EtOAc, washed with aqueous saturatedsodium hydrogencarbonate solution and saturated brine in that order, anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe resulting residue was purified by silica gel column chromatography(eluent: chloroform:methanol=10:1 (v/v)) to obtain methyl5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidyl]carbonyl}oxy)nicotinate(183 mg).

In the same manner as in Reference Example 152, the compound ofReference Example 153 was obtained.

Reference Example 155

Tert-butyl 4-ethynylpiperidine-1-carboxylate (12.5 g) and iodobenzene(12.8 g) was dissolved in THF:TEA=1:1 (v/v) mixed solvent (125 ml), thenat room temperature, copper iodide (455 mg) and palladiumtetrakistriphenylphosphine complex (1.38 g) were added thereto in thatorder, followed by stirring overnight at room temperature. The solventwas evaporated, EtOAc was added to it, and washed with aqueous 1 Mhydrochloric acid solution, water and saturated brine in that order.This was dried over magnesium sulfate, and the solvent was evaporated toobtain a light brown oil. This was purified by silica gel columnchromatography (eluent: hexane:EtOAc=19:1 (v/v)) to obtain tert-butyl4-(phenylethynyl)piperidine-1-carboxylate (15.5 g) as a light brown oil.

4 M hydrogen chloride/EtOAc solution (70 ml) was added to tert-butyl4-(phenylethynyl)piperidine-1-carboxylate (7.0 g), followed by stirringat room temperature for 30 minutes. The solvent was evaporated to obtain4-(phenylethynyl)piperidine hydrochloride (5.4 g) as a white powder.

Example 1

3-Hydroxypyridine (400 mg), TEA (1.17 ml) and DMAP (catalytic amount)were added in that order to a THF (10 ml) solution containingpiperidine-1-carbonyl chloride (745 mg), and then heated at 60° C. for 5hours. The reaction solution was cooled, then water (3 ml) was addedthereto, and extracted with EtOAc. The extract was washed with water,and then dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) toobtain a colorless oil. The resulting oil was dissolved in ethanol, andan ethanol solution of oxalic acid (378 mg) added thereto to obtain acolorless powder. This was recrystallized from hexane/ethanol to obtain(pyridin-3-yl)piperidine-1-carboxylate oxalate (761 mg).

Example 2

A methylene chloride (20 ml) solution containing 3-hydroxypyridine (568mg) and pyridine (724 μl) was dropwise added to a methylene chloride (25ml) solution containing triphosgene (590 mg), followed by stirring atroom temperature for 1 hour. The solvent was evaporated under reducedpressure, the residue was dissolved in pyridine (30 ml), then thecompound (1.2 g) obtained in Reference Example 22 was added thereto,followed by heating at 70° C. for 4 hours. The reaction solution wasconcentrated under reduced pressure, then chloroform and aqueous sodiumhydrogencarbonate solution was added thereto, and the organic layer wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorlesspowder. This was recrystallized from hexane/EtOAc to obtain(pyridin-3-yl)4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (861 mg).

In the same manner as in Example 2, the compounds of Examples 3 to 118,389 to 391, 416 and 417 and Reference Examples 83 to 93 were obtained.

Example 119

A methylene chloride (20 ml) solution containing 3-hydroxypyridine (1.43g) and pyridine (1.46 ml) was dropwise added to a methylene chloride (30ml) solution containing triphosgene (1.48 g), followed by stirring atroom temperature for 1 hour. A methylene chloride (5 ml) solutioncontaining tert-butyl 1-piperazinecarboxylate (2.0 g) and pyridine (0.97ml) was dropwise added to the reaction solution, then pyridine (20 ml)was added thereto, followed by heating at 70° C. for 4 hours. Thereaction solution was concentrated under reduced pressure, diluted withEtOAc, and the organic layer was washed with aqueous saturated sodiumhydrogencarbonate solution, and then dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified through basic silica gel column chromatography(eluent: hexane:EtOAc=4:1 (v/v)) to obtain a colorless solid (3.0 g).

The resulting compound (3.0 g) was dissolved in EtOAc (20 ml)/2-propanol(10 ml), then 4 M hydrogen chloride/EtOAc solution (10 ml) was addedthereto, followed by stirring overnight at room temperature. Thereaction solution was concentrated under reduced pressure, and theresulting solid was washed with EtOAc and dried under reduced pressureto obtain 3-pyridyl 1-piperazinecarboxylate dihydrochloride (2.66 g).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (150 mg),1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0.23 ml) wereadded to a DMF (5 ml) solution containing the resulting compound (190mg) and 4-(cyclooctylmethoxy)benzoic acid (176 mg) prepared fromcyclooctylmethanol with reference to Reference Example 70, followed bystirring overnight at room temperature. The reaction solution wasdiluted with EtOAc, the organic layer was washed with aqueous saturatedsodium hydrogencarbonate solution, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was recrystallized from EtOAc/hexane to obtain 3-pyridyl4-[4-(cyclooctylmethoxy)benzoyl]-1-piperazinecarboxylate (240 mg).

In the same manner as in Example 119, the compounds of Examples 120 to136 were obtained.

Example 137

Potassium tert-butoxide (810 mg) was added to a DMF (10 ml) solutioncontaining 6-chloronicotinonitrile (1.0 g) and 3-chlorobenzyl alcohol(1.0 g), followed by stirring overnight at room temperature. Water wasadded to the reaction solution, and the precipitated solid was collectedby filtration, washed with water and hexane in that order, and driedunder reduced pressure to obtain a brown solid (1.3 g).

An aqueous 5 M sodium hydroxide solution (10 ml) was added to an ethanol(10 ml) solution containing the resulting compound (1.3 g), followed bystirring at 100° C. for 4 hours. After this was cooled to roomtemperature, 1 N hydrochloric acid (56 ml) was added thereto, and theprecipitated solid was collected by filtration, washed with water anddried under reduced pressure to obtain a colorless solid (0.82 g).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (150 mg),1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0.23 ml) wereadded to a DMF (5 ml) solution containing the resulting compound (176mg) and 3-pyridyl 1-piperazinecarboxylate dihydrochloride (166 mg),followed by stirring overnight at room temperature. The reactionsolution was diluted with EtOAc, the organic layer was washed withaqueous saturated sodium hydrogencarbonate solution, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified through basic silica gel columnchromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorlessoil (140 mg).

Oxalic acid (35 mg) was added to a 2-propanol solution containing theresulting compound (140 mg), followed by stirring for 30 minutes. Theprecipitated solid was collected by filtration, washed with2-propanol/hexane, and dried under reduced pressure to obtain 3-pyridyl4-({6-[(3-chlorobenzyl)oxy]-3-pyridyl}carbonyl)-1-piperazinecarboxylate0.5-oxalate (120 mg).

In the same manner as in Example 137, the compound of Example 138 wasobtained.

Example 139

Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) wereadded to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide(686 mg), followed by heating at 80° C. for 2 hours. The reactionsolution was cooled, water (45 ml) was added thereto, and theprecipitated solid was collected by filtration, washed with water anddried to obtain ethyl[4-(aminocarbonyl)phenoxy]acetate (893 mg) as palebrown powder.

The resulting compound (870 mg) was dissolved in THF (10 ml), andethanol (0.274 ml) and an aqueous 1 M sodium hydroxide solution (4.68ml) were added thereto, followed by stirring at room temperature for 4hours. The reaction solution was concentrated under reduced pressure,acidified with an aqueous 1 M hydrochloric acid solution, and theprecipitated solid was collected by filtration and dried to obtain apale brown powder [4-(aminocarbonyl)phenoxy]acetic acid (714 mg).

TEA (0.251 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (259 mg), 1-hydroxybenzotriazole (122 mg) and theabove-produced compound [4-(aminocarbonyl)phenoxy]acetic acid (184 mg)were added to a DMF (5 ml) solution containing 3-pyridyl1-piperidinecarboxylate dihydrochloride (252 mg) obtained in the methodof Example 121, followed by stirring at room temperature for 5 hours. Anaqueous saturated sodium hydrogencarbonate solution was added to thereaction solution, followed by extraction with chloroform. The organiclayer was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), andthe resulting solid was recrystallized from EtOAc/acetonitrile to obtainpyridin-3-yl4-{[4-(aminocarbonyl)phenoxy]acetyl}piperidine-1-carboxylate (274 mg).

In the same manner as in Example 139, the compounds of Examples 140 and141 were obtained.

Example 142

TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to adichloromethane (5 ml) solution containing 3-pyridyl1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirringovernight at room temperature. The reaction solution was diluted withchloroform, the organic layer was washed with aqueous saturated sodiumhydrogencarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography (eluent: chloroform), andthe resulting solid was recrystallized from 2-propanol to obtain3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).

In the same manner as in Example 142, the compound of Example 143 wasobtained.

Example 144

Benzyl chloroformate (91 mg) was added to a pyridine (3 ml) solutioncontaining 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg),followed by stirring at room temperature for 12 hours. The reactionsolution was concentrated under reduced pressure, diluted with EtOAc,and the organic layer was washed with aqueous saturated sodiumhydrogencarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, the residue wasdiluted with 2-propanol (3 ml), and toluenesulfonic acid hydrate (100mg) was added thereto, followed by stirring. The crystal precipitatedwas collected by filtration and recrystallized from 2-propanol to obtainbenzyl 3-pyridyl 1,4-piperazinedicarboxylate tosylate (98 mg).

In the same manner as in Example 144, the compounds of Examples 145 and146 were obtained.

Example 147

10% Palladium-carbon (catalytic amount) was added to a THF (20ml)/2-propanol (20 ml) solution containing 3-pyridyl4-[(4-benzyloxy)benzoyl]-1-piperazinecarboxylate (1.3 g), and in ahydrogen gas atmosphere, this was stirred at room temperature undernormal pressure for 12 hours. The catalyst was removed by filtration,the filtrate was concentrated under reduced pressure, and the resultingsolid was recrystallized from EtOAc/hexane to obtain 3-pyridyl4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (950 mg).

A THF (5 ml) solution containing 3-pyridyl4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (300 mg) and diethylazodicarboxylate (0.62 ml, 40% Tol solution) was dropwise added to a THF(5 ml) solution containing 3-chlorobenzyl alcohol (200 mg) andtriphenylphosphine (360 mg), at 0° C., followed by stirring at roomtemperature for 3 days. The reaction solution was diluted withchloroform, washed with an aqueous saturated sodium hydrogencarbonatesolution, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: chloroform:methanol=95:5(v/v)), and the resulting solid was recrystallized from 2-propanol toobtain 3-pyridyl4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperazinecarboxylate (260 mg).

In the same manner as in Example 147, the compounds of Examples 148 to166 were obtained.

Example 167

Potassium carbonate (270 mg) was added to an acetonitrile (10 ml)solution containing 3-pyridyl4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (530 mg) and methyl3-(bromomethyl)benzoate (450 mg), followed by stirring at 80° C. for 1hour. Water was added to the reaction solution, followed by extractionwith EtOAc. The organic layer was washed with water and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:EtOAc=1:4 (v/v)) to obtain a colorlesssolid (470 mg).

The resulting solid (100 mg) was recrystallized from EtOAc to obtain3-pyridyl4-(4-{[3-(methoxycarbonyl)benzyl]oxy}benzoyl)-1-piperazinecarboxylate(88 mg).

Example 168

4-Ethyl 1-pyridin-3-yl piperidine-1,4-dicarboxylate (0.732 g) wasdissolved in THF (15 ml) and ethanol (8.0 ml), and under ice cooling, anaqueous 1 M sodium hydroxide solution (3.9 ml) was dropwise addedthereto. This was stirred at room temperature for 2 hours, andneutralized with 1 M hydrochloric acid (0.5 ml). The reaction liquid wasconcentrated under reduced pressure, methanol was added to the residue,and the precipitated salt was removed through suction filtration. Thefiltrate was concentrated to obtain1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (0.727 g) as acolorless solid.

The resulting compound (0.60 g) was dissolved in dimethylformamide (10ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.93 g), 1-hydroxybenzotriazole (0.51 g) and cyclohexanemethylamine(0.43 g) were added thereto, followed by stirring at room temperaturefor 15 hours. Water was added to the reaction solution, followed byfurther stirring for 1 hour. Then, sodium hydrogencarbonate solution wasadded thereto, followed by Extraction with EtOAc. The organic layer waswashed with 0.5 M hydrochloric acid and saturated brine in that order.The organic layer was dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=1:4(v/v)) to obtain a colorless powder (0.69 g). This was recrystallizedfrom ethanol and hexane to obtain (pyridin-3-yl)4-{[(cyclohexylmethyl)amino]carbonyl}piperidine-1-carboxylate (261 mg).

In the same manner as in Example 168, the compounds of Examples 169 to192, 383 to 388 and Reference Example 94 were obtained.

Example 193

3-Pyridinyl chlorocarbonate (330 mg) was added to a pyridine (10 ml)solution containing 1-benzyl 2-methyl-1,2-piperazinedicarboxylate (660mg, Beilstein Registry No. 4236331), followed by stirring at 80° C. for7 hours. The reaction solution was concentrated under reduced pressure,diluted with chloroform, and the organic layer was washed with aqueoussaturated sodium hydrogencarbonate solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified through basic silica gel columnchromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorlessoil (700 mg).

An aqueous 1 M sodium hydroxide solution (1.2 ml) was added to a THF (5ml) solution containing the resulting compound (430 mg), followed bystirring at 50° C. for 3 hours. Aqueous 1 M sodium hydroxide solution(0.8 ml) was added thereto, and further heated at 50° C. for 1 hours,then cooled to room temperature, and 1 N hydrochloric acid (2 ml) wasadded thereto. The reaction solution was extracted with EtOAc, theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the precipitated solid was washed with EtOAc/hexane, and dried underreduced pressure to obtain1-[(benzyloxy)carbonyl]-4-[(3-pyridyloxy)carbonyl]-2-piperidinecarboxylicacid (140 mg).

In the same manner as in Example 193, the compounds of Examples 194 and195 were obtained.

Example 196

Pyridin-3-yl4-({[2-(methylamino)phenyl]amino}carbonyl)piperidine-1-carboxylate (0.41g) was dissolved in acetic acid (10 ml), followed by heating underreflux for 2 hours. The solvent was evaporated, and the residue wasrecrystallized from methanol and diethyl ether to obtain (pyridin-3-yl)4-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate (307 mg).

Example 197

Pyridin-3-yl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate(0.249 g) was dissolved in THF (5.0 ml), and under ice cooling, 4 Mhydrogen chloride/EtOAc solution (2.10 ml) was added thereto, followedby stirring at room temperature for 24 hours. The reaction solution wasconcentrated to dryness to obtain pyridin-3-yl4-aminopiperidine-1-carboxylate dihydrochloride (0.280 g).

The resulting compound (0.28 g) was dissolved in dimethylformamide (10ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.28 g), 1-hydroxybenzotriazole (0.16 g), TEA (0.54 ml) and6-phenylhexanoic acid (0.18 g) were added thereto, followed by stirringat room temperature for 15 hours. Water was added to the reactionsolution and further stirred for 1 hour. Then, sodium hydrogencarbonatesolution was added thereto, followed by extraction with EtOAc. Theorganic layer was washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: EtOAc) to obtain a colorless powder. This wasrecrystallized from methanol and diethyl ether to obtain (pyridin-3-yl)4-[(6-phenylhexanoyl)amino]piperidine-1-carboxylate (108 mg).

Example 198

10% Palladium-carbon (catalytic amount) was added to a THF (75ml)/2-propanol (75 ml) solution containing 3-pyridyl4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in ahydrogen gas atmosphere, this was stirred at room temperature undernormal pressure for 24 hours. The catalyst was removed by filtration,and the filtrate was concentrated under reduced pressure, and theresulting solid was washed with EtOAc/hexane, and dried under reducedpressure to obtain 3-pyridyl4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).

Example 199

10% Palladium-carbon (catalytic amount) was added to a THF (75ml)/2-propanol (75 ml) solution containing 3-pyridyl4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in ahydrogen gas atmosphere, this was stirred at room temperature undernormal pressure for 24 hours. The catalyst was removed by filtration,and the filtrate was concentrated under reduced pressure, and theresulting solid was washed with EtOAc/hexane, and dried under reducedpressure to obtain 3-pyridyl4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).

Example 200

Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise addedto a THF (5 ml) solution containing 3-pyridyl4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg),cyclohexylmethanol (87 mg) and triphenylphosphine (200 mg), at 0° C.,followed by stirring at room temperature for 24 hours. The reactionsolution was diluted with chloroform, washed with aqueous saturatedsodium hydrogencarbonate solution, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane:EtOAc=1:1 (v/v)). The resulting oil was dissolved in EtOAc (5ml), 4 M hydrogen chloride/EtOAc solution (1 ml) was added thereto,followed by stirring at room temperature. The solvent was evaporatedunder reduced pressure, and the precipitated solid was washed withEtOAc/2-propanol and dried under reduced pressure to obtain 3-pyridyl4-[3-(cyclohexylmethoxy)phenoxy]-1-piperidinecarboxylate hydrochloride(94 mg).

In the same manner as in Example 200, the compounds of Examples 201 to205 were obtained.

Example 206

Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise addedto a THF (5 ml) solution containing 3-pyridyl4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), 3-chlorobenzylalcohol (110 mg) and triphenylphosphine (200 mg) at 0° C., followed bystirring at room temperature for 24 hours. The reaction solution wasdiluted with chloroform, washed with aqueous saturated sodiumhydrogencarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane:EtOAc=1:3(v/v)). The resulting oil was dissolved in EtOAc (5 ml), and 4 Mhydrogen chloride/EtOAc solution (1 ml) was added thereto, followed bystirring at room temperature. The solvent was evaporated under reducedpressure, and the precipitated solid was recrystallized fromEtOAc/2-propanol to obtain 3-pyridyl4-{4-[(3-chlorobenzyl)oxy]phenoxy}-1-piperidinecarboxylate hydrochloride(45 mg).

In the same manner as in Example 206, the compounds of Examples 207 to212 were obtained.

Example 213

10% Palladium-carbon (catalytic amount) was added to an ethanol (100 ml)solution containing methyl5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinate, andin a hydrogen gas atmosphere, this was stirred overnight at roomtemperature under normal pressure. The catalyst was removed byfiltration, the resulting filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=15:1 (v/v)) to obtain acolorless oil (1.08 g).

2.2 M diethyl azodicarboxylate (1.01 ml) and triphenylphosphine (581 mg)were added to a THF (20 ml) solution containing the resulting compound(450 mg) and 3-cyclohexyl-1-propanol (315 mg), followed by heating at50° C. for 22 hours. Water was added to the reaction solution, followedby extraction with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=2:1 (v/v)) toobtain methyl5-[({4-[4-[(3-cyclohexylpropoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinate(242 mg).

In the same manner as in Example 213, the compounds of Examples 214 to216 were obtained.

Example 217

10% Palladium-carbon (catalytic amount) was added to a THF (10 ml)solution containing5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid(200 mg), and in a hydrogen gas atmosphere, this was stirred at roomtemperature under normal pressure for 3 hours. The catalyst was removedby filtration, and the resulting filtrate was concentrated under reducedpressure to obtain5-[({4-[4-(hydroxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid(55 mg).

Example 218

The compound (4.0 g) of Example 29, obtained in the same method as inExample 2, was dissolved in THF (30 ml) and methanol (15 ml), and underice cooling, an aqueous 1 M sodium hydroxide solution (12 ml) wasdropwise added thereto. This was stirred at room temperature for 30minutes, and then under ice cooling, this was neutralized with 1 Mhydrochloric acid (12 ml). The colorless solid precipitated wascollected by filtration to obtain5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinicacid (3.52 g).

In the same manner as in Example 218, the compounds of Examples 219 to224 and Examples 226 to 243 were obtained.

Example 225

A methylene chloride (30 ml) solution containing methyl5-hydroxynicotinate (2.20 g) and pyridine (4 ml) was dropwise added to amethylene chloride (50 ml) solution containing triphosgene (1.56 g),followed by stirring at room temperature for 1 hour. The solvent wasevaporated under reduced pressure, the residue was dissolved in pyridine(50 ml), and 4-(2-phenylethyl)piperidine hydrochloride (2.70 g) wasadded thereto, followed by heating overnight at 80° C. The reactionsolution was concentrated under reduced pressure, then EtOAc and anaqueous sodium hydrogencarbonate solution were added thereto. Theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) toobtain a colorless powder. This was recrystallized from hexane/EtOAc toobtain methyl5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate (3.95 g).

Methyl 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate(3.95 g) was dissolved in THF (32 ml) and methanol (16 ml), and underice cooling, aqueous 1 M sodium hydroxide solution (16 ml) was dropwiseadded thereto. This was stirred at room temperature for 30 minutes, andunder ice cooling, this was neutralized with 1 M hydrochloric acid (16ml). The colorless solid precipitated was collected by filtration, andrecrystallized from methanol/water to obtain5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid (3.70g).

Example 244

The compound of Example 219,5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinicacid (0.50 g) was dissolved in DMF (8.0 ml), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 g),1-hydroxybenzotriazole (0.22 g) and glycine tert-butyl ester (0.21 g)were added thereto, followed by stirring at room temperature for 15hours. Water was added to the reaction solution, followed by stirringfor 1 hours. Then, sodium hydrogencarbonate solution was added thereto,followed by extraction with EtOAc. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) toobtain a colorless oil (0.444 g).

The resulting compound (0.444 g) was dissolved in methylene chloride(5.0 ml), and under ice cooling, TFA (1.15 ml) was added thereto. Thiswas stirred at that temperature for 24 hours, and then the reactionliquid was concentrated to obtain a yellow solid. This wasrecrystallized from ethanol and diethyl ether to obtain{[(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)carbonyl]amino}aceticacid (348 mg).

According to the amidation as in Example 244, the compounds of Examples245 to 257 were obtained.

Example 258

Water (4 ml), sodium carbonate (337 mg) and tetrakistriphenylphosphinepalladium (115 mg) were added in that order to a dimethoxyethane (12 ml)solution containing the compound (400 mg) of Example 54 and[3-(aminocarbonyl)phenyl]boronic acid (176 mg), followed by heating at80° C. for 5 hours. The reaction solution was cooled and diluted withEtOAc. The organic layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane:EtOAc=1:5 (v/v)) to obtain5-[3-(aminocarbonyl)phenyl]pyridin-3-yl-4-benzylpiperidine-1-carboxylate(205 mg).

In the same manner as in Example 258, the compounds of Examples 259,265, 266 and 399 were obtained.

Example 260

A 4 M hydrogen chloride/dioxane solution (1.8 ml) was added to a THF (10ml) solution containing 5-[(tert-butoxycarbonyl)amino]pyridin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (174 mg),followed by stirring at 60° C. for 4 hours. The solvent was evaporatedunder reduced pressure to obtain 5-aminopiperidin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}pyridine-1-carboxylate hydrochloride(74 mg).

Example 261

An aqueous 1 M sodium hydroxide solution (3.24 ml) was added to a THF(10 ml) solution containing5-[4-(ethoxycarbonyl)piperidin-1-yl]pyridin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (240mg), followed by stirring at 60° C. for 5 hours. 1 M hydrochloric acid(3.24 ml) was added to the reaction solution and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform:methanol=10:1 (v/v)). Theresulting oil was dissolved in ethanol/water, then oxalic acid (24 mg)was added thereto for crystallization to obtain1-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)piperidine-4-carboxylicacid oxalate (93 mg).

Example 262

TFA (1.0 ml) was added to a methylene chloride (10 ml) solutioncontaining 5-[(2-tert-butoxy-2-oxoethoxy)methyl]pyridin-3-yl4-{4-[(3-(3-fluorobenzyl)oxy]phenoxy}piperidin-1-carboxylate (333 mg),followed by stirring overnight at room temperature. The solvent wasevaporated under reduced pressure to obtain[(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl}methoxy]aceticacid (232 mg).

Example 263

An aqueous 1 M sodium hydroxide solution (7.65 ml) was added to a THF(20 ml) solution containing 5-[(acetoxy)methyl]pyridin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (1.10g), followed by stirring at 65° C. for 3 hours. The reaction liquid wasneutralized with 1 M hydrochloric acid, followed by extraction withchloroform and drying over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: chloroform:methanol=12:1(v/v)) to obtain 5-(hydroxymethyl)piperidin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (770 mg).

Example 264

An aqueous 1 M sodium hydroxide solution (1.11 ml) was added to a THF (5ml) solution containing5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]pyridin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (158 mg),followed by stirring at 60° C. for 3 hours. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain(2E)-3-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)acrylicacid (88 mg).

Example 267

(a) Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) wasadded to an acetonitrile (10 ml) solution of3-[2-(4-piperidyl)ethyl]benzonitrile hydrochloride (475 mg) and TEA(0.58 ml), followed by stirring overnight at room temperature. Thereaction liquid was diluted with EtOAc, followed by washing with anaqueous saturated sodium hydrogencarbonate solution and drying overanhydrous magnesium sulfate. The solvent was evaporated, the resultingresidue was subjected to basic silica gel column chromatography (eluent:hexane:EtOAc=1:1 (v/v)) and the side-product, nitrophenol was removed.Then, this was purified by silica gel column chromatography (eluent:hexane:EtOAc=3:2 (v/v)) to obtain methyl5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284mg).

(b) An aqueous 1 M sodium hydroxide solution (0.69 ml) was added to aTHF (5 ml)/water (4 ml) solution of methyl5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (272mg), followed by stirring overnight at room temperature. 1 Mhydrochloric acid (0.69 ml) was added to the reaction liquid, and thecrystal precipitated was collected by filtration. The crystal was washedwith a hot methanol/water solution, and dried to obtain5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid(240 mg).

In the same manner as in the step (a) in Example 267, the compounds ofReference Examples 149 to 150, and Examples 268 to 272, 392, 396, 400,402, 413, 419, 421 and 422 were obtained.

According to the same method containing the step (b) after the step (a)as in Example 267, the compounds of Examples 273 to 317, 393 to 395,401, 403, 405, 406, 414 and 418 were obtained.

Example 318

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (62 mg),1-hydroxybenzotriazole (43 mg), ammonium chloride (43 mg) and TEA (0.038ml) were added to a DMF (3.0 ml) solution of5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid(102 mg), followed by stirring overnight at room temperature. An aqueoussaturated sodium hydrogencarbonate solution was added to the reactionliquid, and the crystal precipitated was collected by filtration anddried. The resulting crystal was recrystallized from EtOAc/hexane togive 5-(aminocarbonyl)-3-pyridyl4-[2-(3-cyanophenyl)ethyl]-1-piperidinecarboxylate (81 mg).

In the same manner, the compounds of Examples 319 to 382, 397, 398, 404,408 to 412, 415, 420 and 423 were obtained.

Example 407

Under ice cooling, potassium tert-butoxide (2.73 g) was added to a DMF(50 ml) solution of triphenyl(pyridin-4-ylmethyl)phosphonium chloridehydrochloride (4.75 g) and tert-butyl 4-formylpiperidine-1-carboxylate(1.91 g), followed by stirring overnight at room temperature. Thereaction liquid was diluted with EtOAc, washed with water and saturatedbrine in that order, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a whitesolid (2.05 g).

The resulting solid (2.04 g) was dissolved in EtOAc (30 ml), and 10%palladium-carbon (200 mg) was added thereto, followed by stirring in thepresence of hydrogen at room temperature for 3 hours. The catalyst wasremoved by filtration, the solvent was concentrated, and the residue waspurified by silica gel column chromatography (eluent: hexane:ethylacetate=1:1 (v/v)) to obtain tert-butyl4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.70 g) as a whitesolid.

A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100mg) were added to an ethanol (25 ml) solution of tert-butyl4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followedby stirring in the presence of hydrogen (3.5 atm) for 24 hours. This waspurged with argon, diluted with methanol, filtered through Celite, andconcentrated under reduced pressure. The solid precipitated was washedwith EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg)as a white solid.

2-(Dicyclohexylphosphino)biphenyl (71 mg) and(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium (93 mg) were added toa toluene (10 ml) suspension of tert-butyl4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (1.13g), 2-chloro-6-methylpyridine (431 mg) and sodium tert-butoxide (487mg), followed by stirring at 120° C. for 1 hour. The reaction liquid wasleft cooled, then an aqueous saturated sodium carbonate solution wasadded thereto, followed by extraction with EtOAc. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.Then, the solvent was evaporated and the residue was purified by silicagel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtaintert-butyl4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate(660 mg) as a red oil.

A 4 M hydrogen chloride/EtOAc solution (2 ml) was added to an EtOAc (10ml) solution of tert-butyl4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate(650 mg), followed by stirring at room temperature for 2 days. Thereaction liquid was concentrated to obtain2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridinedihydrochloride (644 mg) as a yellow amorphous substance.

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added toan acetonitrile (10 ml) solution of2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridinedihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at roomtemperature for 3 hours. The reaction liquid was diluted with EtOAc,washed with an aqueous saturated sodium hydrogencarbonate solution, anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe resulting residue was purified by silica gel column chromatography(eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate(424 mg).

An aqueous 1 M sodium hydroxide solution (0.45 ml) was added to a THF (5ml) solution of methyl5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate(208 mg), followed by stirring overnight at room temperature. Thereaction liquid was concentrated to obtain sodium5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate(158 mg).

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (103 mg),1-hydroxybenzotriazole (90 mg) and ammonium chloride (119 mg) were addedto a DMF (10 ml) solution of sodium5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate(210 mg), followed by stirring overnight at room temperature.

The reaction liquid was diluted with EtOAc, washed with an aqueoussaturated sodium hydrogencarbonate solution and saturated brine in thatorder, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the resulting residue wasrecrystallized from EtOAc/hexane to obtain 5-(aminocarbonyl)pyridin-3-yl4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate(150 mg).

Example 438 Screening for FAAH Activity-Inhibiting Substance with RatBrain Homogenate (1) Preparation of Rat Brain Homogenate:

The head of a 10-week age SD-line male rat (Japan SLC) was cut off, andits cerebrum was taken out and weighed. Five times by volume its weightof an ice-cooled buffer (50 mM Tris-HCl (pH 7.4), 0.32 M sucrose) wasadded, and this was homogenized with a homogenizer in ice to give auniform suspension. This was centrifuged (1500×g, 4° C., 15 minutes),and the supernatant was again centrifuged (15000×g, 4° C., 20 minutes)to obtain a precipitate. Further, using an ultrasonic wave generator(UR-20P, Tommy Seiko), this was ultrasonicated (power dial 4) for 5seconds. The protein concentration of the resulting homogenate wasmeasured according to a dye-coupling method (protein assay CBB solution,Nacalai Tesque). Using a buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1mg/ml BSA, 100 mM NaCl), the rat brain suspension was diluted so thatits protein concentration could be 60 μg/ml, thereby preparing an enzymesolution.

(2) Screening for FAAH Activity-Inhibiting Substance:

A substrate solution was prepared, comprising 2 μCi/ml radiolabeledanandamide (Anandamide [ethanolamine 1-³H] (American RadiolabeledChemical)), 8 μM anandamide (Funakoshi), 50 mM Tris-HCl (pH 8.0), 1 mMEDTA, 0.1 mg/ml BSA and 100 mM NaCl. Test substance solutions wereprepared, dissolved in DMSO to have a concentration of from 1 nM to 100μM. 50 μl of the substrate solution and 1 μm of the test substancesolution were added to 50 μl of the enzyme solution, and left for 1hour. As a control, DMSO was used in place of the test substancesolution. To this, added was 200 μl of a 1:1 (by volume) solution ofchloroform/methanol, followed by vortexing. This was centrifuged (15000rpm, 2 minutes), whereby the decomposed product ethanolamine(ethanolamine 1-³H) was separated in the upper layer (water/methanollayer) and the unreacted radiolabeled anandamide (Anandamide[ethanolamine 1-³H]) was in the lower layer (chloroform layer). 30 μl ofthe upper layer was transferred into a 96-well organic solvent-resistantwhite microplate (PicoPlate-96; Perkin Elmer), 150 μl of Microscint-20(Perkin Elmer) was added thereto, and this was measured with amicroplate scintillation counter (TopCount™; Beckman). As compared withthe control, the substance that gave a decreased value was selected asan FAAH activity-inhibiting substance.

(3) Measurement of IC₅₀ Value of FAAH Activity-Inhibiting Substance:

A test compound was dissolved in DMSO to have a varying concentration offrom 1 nM to 100 μM to prepare test substance solutions. According tothe method mentioned above, the compound was analyzed for its influenceon FAAH activity. As a control, DMSO was used. A measured value of acase where a buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA,100 mM NaCl) was reacted in place of the enzyme solution was subtractedfrom every measured value. Based on the measured value of the control,100%, IC₅₀ value of the test substance was obtained. For example, IC₅₀of the compounds of Examples 2, 151, 225, 228, 273, 324, 325 and 359 was0.14 nM, 27 nM, 0.37 nM, 0.19 nM, 0.65 nM, 0.54 nM, 2.5 mM and 1.3 nM,respectively.

The above results confirm that, when a test substance is contacted witha homogenate of a tissue that expresses FAAH or functional FAAH and whenthe test substance-dependent FAAH activity change is measured, then itmay be screened for an FAAH activity-inhibiting substance, or that is, aremedy for urinary frequency and urinary incontinence, a remedy foroveractive bladder and/or a remedy for pain.

Example 439 Screening for FAAH Activity-Inhibiting Substance with HumanBladder Epithelial Cancer-Derived Cell (1) Screening for FAAHActivity-Inhibiting Substance:

Human bladder epithelial cancer-derived cell line 5678 cells (HTB-9;ATCC) were seeded on a 48-well cell culture plate in an amount of 1×10⁵cell/well, using 10% fetal bovine serum (HyClone)-containing RPMI1640medium (Invitrogen). After incubated at 37° C. for at least 12 hours,the cells were washed with 400 μl/well of a buffer (Hank's Balanced SaltSolution, 20 mM Hepes-NaOH (pH 7.4)). A test substance dissolved in DMSOwas added to a substrate solution (the above buffer containing 3 μCi/mlradiolabeled anandamide (Anandamide [ethanolamine 1-3H]) and 10 μManandamide) so as to have a concentration of from 0.003 nM to 30 nM. Asa control, DMSO alone was added. 100 μl/well of the substrate solutionwas added to the above cells, and incubated in a CO₂ incubator at 37° C.for 30 minutes. Next, the cell culture plate was transferred onto ice,and the substrate solution was removed by suction; and 75 μl/well of acytolytic solution (the above buffer containing 0.5% Triton X-100, and10 μM of FAAH-inhibitory activity-having compound,3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597; Cayman chemical;Kathuria et al., Nature Med., Vol. 9, pp. 76-81, 2003)) was addedthereto, followed by stirring. The resulting cell lysate in every wellwas individually transferred into a 1.5 ml sample tube, to which wasadded 150 μl of 1:1 (by volume) chloroform/methanol solution, followedby vortexing. This was centrifuged (15000 rpm, 2 minutes), whereby thedecomposed product, ethanolamine (ethanolamine 1-³H) was separated inthe upper layer (water/methanol layer) and the unreacted radiolabeledanandamide was in the lower layer (chloroform layer). 25 μl of the upperlayer was transferred into a 96-well organic solvent-resistant whitemicroplate (PicoPlate-96; Perkin Elmer), 150 μl of Microscint-20 (PerkinElmer) was added thereto, and this was measured with a microplatescintillation counter (TopCount™; Beckman). As compared with thecontrol, the substance that gave a decreased value was selected as anFAAH activity-inhibiting substance.

(2) Measurement of IC₅₀ Value of FAAH Activity-Inhibiting Substance:

A test compound dissolved in DMSO to have a concentration of 10 mM wasdissolved in the substrate solution so as to have a varyingconcentration of from 0.003 nM to 30 μM. According to the methodmentioned above, the compound was analyzed for its influence on FAAHactivity. As a negative control, DMSO was used. As a positive control,URB597 was added to the substrate solution to have a concentration of 10μM. Based on the measured value of the positive control, 0%, and on themeasured value of the negative control, 100%, IC₅₀ value of the testsubstance was obtained. The test results are shown in Table 64.

The above results confirm the excellent FAAH inhibitory activity oftypical compounds of the present invention. In addition, these indicatethat, when a test substance is contacted with a cell that expresses FAAHor functional FAAH and when the test substance-dependent FAAH activitychange is measured, then it may be screened for an FAAHactivity-inhibiting substance, or that is, a remedy for urinaryfrequency and urinary incontinence, a remedy for overactive bladderand/or a remedy for pain.

Example 440 Screening for FAAH Activity-Inhibiting Substance with TissueHomogenate of Rat Administered with Test Substance (1) Administration toRat, and Preparation of Tissue Homogenate:

A test substance suspended in 0.5% methyl cellulose (MC) solution wasorally administered to two 9-week age Wistar male rats (Japan SLC) at adose of from 1 to 3 mg/kg. As a control, 0.5% MC solution wasadministered to other two rats. After 30 minutes, the blood wascollected from each rat under ether anesthesia through its aorta. Withthat, the head of each rat was cut off, and its cerebrum was taken out.

3 ml of the collected blood was diluted with the same amount ofphysiological saline water, and gently put on 3 ml of ahemocyte-separating agent (Nycoplep; AXIS-SHIELD) in a centrifugal tube.This was centrifuged (400×g, 20 minutes) to collect the monocytic layer.The resulting monocytes were washed twice with physiological saline, andfrozen and stored at −20° C. until their use for measurement.

To the collected rat brain, added was five times by volume its weight ofan ice-cooled buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA), and this washomogenized with a homogenizer in ice to give a uniform suspension.Further, using an ultrasonic wave generator (UR-20P (power dial 4),Tommy Seiko), this was ultrasonicated for 5 seconds. To the above frozenmonocytes, added was 1001 of an ice-cooled buffer (50 mM Tris-HCl (pH8.0), 1 mM EDTA), and using an ultrasonic wave generator (UR-20P (powerdial 4), Tommy Seiko), this was ultrasonicated for 5 seconds. Theprotein concentration of each of the homogenates of brain and monocyteswas measured according to a dye-coupling method (protein assay CBBsolution, Nacalai Tesque). Using a buffer (50 mM Tris-HCl (pH 8.0), 1 mMEDTA, 0.1 mg/ml BSA, 100 mM NaCl), the homogenates of brain andmonocytes were diluted so that their protein concentration could be 80μg/ml and 400 μg/ml thereby preparing enzyme solutions.

(2) Measurement of FAAH Activity:

50 μl of the enzyme solution was reacted with 50 μl of a substratesolution (2 μCi/ml radiolabeled anandamide (Anandamide [ethanolamine1-³H] (American Radiolabeled Chemical)), 8 μM anandamide (Funakoshi), 50mM Tris-HCl (pH 8.0), 1 mM EDTA) added thereto, at room temperature for1 hour. 200 μl of a 1:1 (by volume) solution of chloroform and methanolwas added to it, followed by vortexing. This was centrifuged (12000×g, 2minutes), whereby the decomposed product ethanolamine (ethanolamine1-³H) was separated in the upper layer (water/methanol layer) and theunreacted radiolabeled anandamide (Anandamide [ethanolamine 1-³H]) wasin the lower layer (chloroform layer). 25 μl of the upper layer wastransferred into a 96-well organic solvent-resistant white microplate(PicoPlate-96; Perkin Elmer), 150 μl of Microscinti-20 (Perkin Elmer)was added thereto, and this was measured with a microplate scintillationcounter (TopCount™; Beckman).

Based on the FAAH activity of the control, test substance-free, ratbrain or monocyte homogenate, 100%, and on the FAAH activity of thetissue homogenate-free buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1mg/ml BSA, 100 mM NaCl), 0%, the relative value (%) of the FAAH activityof the tissue homogenate of the rat administered with the test substancewas obtained. The substance that decreased the relative value of FAAHactivity was selected as an FAAH activity-inhibiting substance.

The above results confirm that, when a test substance is administered toa test animal and when the test substance-dependent FAAH activity changein the tissue homogenate of the animal is measured, then it may bescreened for an FAAH activity-inhibiting substance, or that is, a remedyfor urinary frequency and urinary incontinence, a remedy for overactivebladder and/or a remedy for pain.

Example 441 Effect of Compound to Cyclophosphamide (CPA)-Induced UrinaryFrequency in Rat

Compounds were tested for their bladder irritation-relieving effect,using pathologic models. It is known that systemic administration ofcyclophosphamide (CPA) converts the compound into its metabolite,acrolein, and, as existing in urine, this injures the bladder mucosa. Inrats, CPA administration induces bladder pain or urinary frequencyaccompanied by hemorrhagic cystitis, and therefore using such rats, itis possible to evaluate the potency of drug for these symptoms. In thisexperiment, used were 9-week age Wistar female rats (Charles River). CPA(100 mg/kg) was intraperitoneally administered to the rats, and after 2days, the rats were tested. A test compound was orally administered(p.o.) to the rats; and after 15 minutes, distilled water (30 ml/kg) wasforcedly orally administered thereto. The rats were put in a metaboliccage, and their urine was continuously measured for 1 hour. The overallurine amount was divided by the overall urination frequency, and theeffective bladder capacity was thus calculated. As a result, in thegroup administered with the solvent, 0.5% methyl cellulose (MC), theeffective bladder capacity reduced, and the rats showed urinaryfrequency. In oral administration, effective dose of compounds ofExamples 2, 218 and 261 was 3 mg/kg; that of compounds of Examples 225,228, 273, 313, 324, 325 and 359 was 1 mg/kg. These compounds increasedthe reduced effective bladder capacity and relieved the condition ofurinary frequency.

Example 442 Anti-Allodynia Effect of Compounds for L5/L6 SpinalNerve-Ligated Rat (Neuropathic Pain Model)

A 5 to 6-week age male SD rat was subjected to operation of ligating itsleft-side L5 and L6 spinal nerves with silk threads. For evaluating theanalgesic effect of a test substance, employed was a von Frey hair test.Briefly, the hindpaw of the animal was picked with hair, whereupon theminimum strength of the hair for limb withdrawal response was referredto as the response threshold (log gram) to the mechanical stimulation.In the preliminary test, it was confirmed that the response threshold ofthe operated paw of the animal remarkably lowered within 7 to 14 daysafter the operation (under allodynia), and the anti-allodynia effect ofthe test compound was evaluated on any day within 7 to 14 days after theoperation. On the day before the test date, the response thresholdbefore test compound administration was measured. The test animals wereso grouped that the mean value difference and fluctuation in thethreshold before test compound administration in the groups could besmall. In the evaluation test of test compounds, the response thresholdvalue after test compound administration was measured. The test compoundwas orally administered 60 minutes before the response threshold valuemeasurement. Based on the response thresholds of operated andnon-operated paws in the solvent-administered group, 0% and 100%,respectively, the potency of the test compound for its anti-allodyniaeffect was calculated. As a result, in 10 mg/kg oral administration ofthe compound of Example 126, it showed an anti-allodynia potency of 74%.

TABLE 1 Rex MS m/z No. Str (M + H)⁺ 1

192:FAB 2

284:FAB 3

284:FAB 4

222:ESI 5

236:ESI 6

250:ESI 7

221:FAB 8

235:FAB 9

249:FAB 10

221:FAB 11

235:FAB

TABLE 2 Rex MS m/z No. Str (M + H)⁺ 12

235:FAB 13

249:FAB 14

221:FAB 15

263:FAB 16

340:ESI 17

213:FAB 18

213:FAB 19

291:FAB 20

277:FAB 21

245:FAB 22

192:FAB

TABLE 3 Rex MS m/z No. Str (M + H)⁺ 23

206:FAB 24

296:ESI 25

220:FAB 26

263:FAB 27

263:FAB 28

297:FAB 29

302:FAB 30

314:FAB 31

290:FAB 32

264:ESI 33

268:ESI

TABLE 4 Rex MS m/z No. Str (M + H)⁺ 34

302:FAB 35

309:FAB 36

304:FAB 37

303:FAB 38

305:FAB 39

298:FAB 40

248:ESI 41

318:FAB 42

318:FAB 43

350:FAB 44

332:FAB

TABLE 5 Rex MS m/z No. Str (M + H)⁺ 45

357:FAB 46

366:FAB 47

338:FAB 48

352:FAB 49

192:ESI 50

235:FAB 51

220:ESI 52

206:ESI 53

232:ESI 54

303:FAB

TABLE 6 Rex MS m/z No. Str (M + H)⁺ 55

233:ESI 56

258:ESI 57

231:FAB 58

233:FAB 59

303:FAB 60

269:FAB 61

318:FAB 62

351:ESI 63

318:FAB 64

365:FAB 65

264:FAB

TABLE 7 Rex MS m/z No. Str (M + H)⁺ 66

264:FAB 67

303:FAB 68

315:FAB 69

317:FAB 70

317:FAB 71

297:FAB 72

320:FAB 73

139:ESI 74

181:ESI

TABLE 8 Rex MS m/z No. Str (M + H)⁺ 75

196:ESI 76

251:ESI 77

140:ESI 78

209:ESI 79

182:ESI 80

240:ESI 81

180:ESI 82

168:ESI 83

369:ESI 84

370:FAB 85

383:ESI

TABLE 9 Rex MS m/z No. Str (M + H)⁺ 86

412:FAB 87

483:FAB 88

384:FAB 89

538:ESI 90

567:ESI 91

483:ESI 92

493:ESI 93

522:ESI 94

251:ESI

TABLE 10 MS m/z (M + H)⁺ or Rex (M − H)⁻ or No. Str (M)⁺ FAB or ESI orEI 95

215(M + H)⁺ FAB 96

268, 270(M + H)⁺ FAB 97

208(M + H)⁺ FAB 98

220(M + H)⁺ FAB 99

224(M + H)⁺ FAB 100

215(M + H)⁺ FAB 101

215(M + H)⁺ FAB 102

348(M + H)⁺ FAB 103

348(M + H)⁺ ESI 104

332(M − H)⁻ ESI 105

332(M − H)⁻ ESI 106

333(M + H)⁺ ESI

TABLE 11 MS m/z (M + H)⁺ or Rex (M − H)⁻ or No. Str (M)⁺ FAB or ESI orEI 107

375(M + H)⁺ ESI 108

389(M + H)⁺ ESI 109

377(M − H)⁻ API 110

375(M − H)⁻ API 111

361(M + H)⁺ ESI 112

387(M + H)⁺ FAB 113

401(M + H)⁺ FAB 114

377(M + H)⁺ ESI 115

389(M + H)⁺ ESI 116

387(M + H)⁺ ESI 117

478(M + H)⁺ ESI 118

479(M + H)⁺ FAB

TABLE 12 MS m/z (M + H)⁺ or Rex (M − H)⁻ or No. Str (M)⁺ FAB or ESI orEI 119

359(M + H)⁺ ESI 120

233(M + H)⁺ FAB 121

247(M + H)⁺ FAB 122

275(M + H)⁺ ESI 123

289(M + H)⁺ ESI 124

315(M + H)⁺ FAB 125

279(M + H)⁺ ESI 126

277(M + H)⁺ ESI 127

261(M + H)⁺ FAB 128

287(M + H)⁺ ESI 129

301(M + H)⁺ ESI 130

303(M + H)⁺ ESI

TABLE 13 MS m/z (M + H)⁺ or Rex (M − H)⁻ or No. Str (M)⁺ FAB or ESI orEI 131

378(M + H)⁺ ESI 132

379(M + H)⁺ ESI 133

233(M + H)⁺ ESI 134

260(M)⁺ ESI 135

288(M + H)⁺ ESI 136

259(M + H)⁺ ESI 137

286(M + H)⁺ ESI 138

378(M + H)⁺ ESI 139

379(M + H)⁺ ESI 140

266(M + H)⁺ FAB 141

291(M + H)⁺ FAB 142

267(M + H)⁺ FAB 143

302(M + H)⁺ FAB

TABLE 14 MS m/z (M + H)⁺ or(M − H)⁻ Rex or(M)⁺ No. Str FAB or ESI or EI144

338(M + H)⁺ ESI 145

338(M + H)⁺ FAB 146

339(M + H)⁺ ESI 147

341 (M + Na)⁺ ESI 148

261(M + H)⁺ ESI 149

466(M + H)⁺ FAB 150

480(M + H)⁺ ESI 151

438(M + H)⁺ ESI 152

427(M + H)⁺ ESI 153

481(M + H)⁺ FAB

TABLE 15 MS m/z (M + H)⁺ or(M − H)⁻ Rex or(M)⁺ No. Str FAB or ESI or EI154

338(M + H)⁺ ESI 155

186(M + H)⁺ ESI

TABLE 16

Ex No. T R¹ R² R⁴ Sal 001 CH H H H oxal 002 CH 4-(3-FPhCH₂O)PhO H H free003 CH 4-(3-FPhCH₂O)PhCO H H free 004 N 4-(3-FPhCH₂O)PhCO H H oxal 005 N4-cHexCH₂OPhCO H H free 006 N 4-cHex(CH₂)₂OPhCO H H free 007 N4-cHepCH₂OPhCO H H free 008 N 4-PhCH₂OPhCO H H free 009 CH 4-cHexCH₂OPhOH H free 010 CH PhCH₂ H H oxal 011 CH 3-PhCH₂OPhO H H free 012 CH4-PhCH₂OPhO H H free 013 CH 4-(3-FPhCH₂O)PhO H 6′-Me HCl 014 CH PhCO H Hfree 015 CH 4-FPh H H free 016 CH PhCONH H H free 017 N Ph(CH₂)₂ H Hfree 018 CH

H H HCl 019 CH

H H free 020 CH

H H HCl 021 CH PhO H H HCl 023 N Ph H H free 024 CH 4-H₂NCOPhO H H free

TABLE 17

Ex No. T R¹ R² R⁴ Sal 025 CH 4-H₂NCOCH₂PhO H H free 026 CH4-H₂NCO(CH₂)₂PhO H H free 027 CH 3-H₂NCOPhO H H oxal 028 CH3-H₂NCOCH₂PhO H H oxal 029 CH 4-(3-FPhCH₂O)PhO H 5′-COOMe free 030 CH4-(3-FPhCH₂O)PhO H 5′-NMe₂ HCl 031 CH 4-cHexCH₂N(Me)PhO H H 2HCl 033 NPh(CH₂)₅ H H 2HCl 034 N 4-PhCH₂OPh H H free 035 CH Ph(CH₂)₂ H H HCl 036CH PhCH₂O H H HCl 037 C Ph 4-HO H HCl 039 C Ph 4-Ac H free 040 CH Ph H HHCl 041 CH 4-H₂NCOPhOCH₂ H H free 042 CH 4-(3-FPhCH₂O)PhO H 5′-Cl free043 CH 4-H₂NCOPhO(CH₂)₂ H H free 044 CH 4-(3-FPhCH₂O)PhO H 5′-Br free045 CH 4-(3-FPhCH₂O)PhO H 5′-Mo4 HCl 046 CH 4-H₂NCOPhCH₂O H H free 047CH PhCH₂NHCO H H free 048 N 3-PhCH₂OPh H H 2HCl 049 N Ph(CH₂)4 H H free050 N tBuOCO H H free 051 CH 2-Cl-4-PhCH₂OPhO H H HCl 052 CH PhCH₂ H6′-Me HCl 053 CH PhCH₂O(CH₂)₂ H H HCl 054 CH PhCH₂ H 5′-Br free 055 CHPhCH₂ H 6′-CH₂OMe free 056 CH 4-(3-FPhCH₂O)PhO H 5′-N(Me)(CH₂)₂NMe₂ 2HCl057 CH 2-H₂NCOPhO H H oxal 058 N 4-(3-FPhCH₂O)PhSO₂ H H free 059 CH Ph₂(HO)C H H HCl 060 CH 3-HOPh H H free 061 CH 4-(3-FPhCH₂O)PhO H5′-(CH₂)₂COOMe free 062 N Ph(CH₂)₂OCO H H free 063 CH 4-H₂NCOPh(CH₂)₂ HH free 064 CH PhCH₂NHCOCH₂ H H HCl

TABLE 18

Ex No. T R¹ R² R⁴ Sal 066 CH 1-MeBenzIM2(CH₂)₃ H H free 067 C Ph 4-NC HHCl 068 CH 2-oxoBenzIM 1 H H free 069 CH 4-H₂NCOPhO(CH₂)₃ H H free 070CH 3-Cl-4-PhCH₂OPhO H H oxal 071 CH 4-[3-FPhSO₂N(Me)]PhO H H HCl 072 NPhCH₂OCO 3-H₂NCO H HCl 073 CH 4-(3-FPhCH₂O)PhO H 5′-(4-EtOCOPIPE1)- oxal074 C PhCH₂ 4-HO H HCl 075 N 4-BuNHCOCH₂OPhCO H H p-tol 076 CH4-(3-FPhCH₂O)PhS H H p-tol 077 CH 3-EtOCOCH₂OPh H H oxal 078 CH3-PhCH₂OPh H H oxal 079 CH 4-PhCH₂OCOPhO(CH₂)₂ H H free 080 CH4-(3-FPhCH₂O)PhSO₂ H H free 081 CH PhCH₂OCH₂ H H oxal 082 CH 4-PhCH₂OPhOH 5′-COOMe free 083 CH 3-(3-H₂NCOPh)PhO H H HCl 084 N Ph(CH₂)₂ 3-oxo Hfree 085 N Ph(CH₂)₂ H 5′-Cl free 086 N Ph(CH₂)₂ H 5′-COOMe free 087 CH6-ClPy3O H H free 088 CH 4-PhCH₂OPhSO₂ H H free 089 CH4-(3-NCPhCH₂O)PhSO₂ H H free 090 CH 4-cHexCH₂OPhSO₂ H H free 091 CH4-cHex(CH₂)₂OPhSO₂ H H free 092 CH 6-ClPy2O H H HCl 093 CH6-(3-FPhCH₂O)Py2O H H oxal 094 CH 6-(3-H₂NCOPh)Py2O H H free 095 CH4-(3-ClPhCH₂O)PhSO₂ H H free 096 N 4-H₂NCOPhCH₂OCO H H free 097 CH4-(3-FPhCH₂O)PhO H 5′-Me free 098 CH 4-Me₂NCOPhO(CH₂)₃ H H p-tol 099 CH4-MeNHCOPhO(CH₂)₃ H H free 100 CH 4-(3-FPhCH₂O)PhO H 5′-CH₂OAc oxal 101CH 3-(3-FPhCH₂O)PhS H H p-tol

TABLE 19

Ex No. T R¹ R² R⁴ Sal 102 CH 6-[cHex(CH₂)₂O]Py2O H H oxal 103 CH5-(3-FPhCH₂O)Py2O H H oxal 105 CH 3-(3-FPhCH₂O)PhSO₂ H H free 106 CH4-NCPhO(CH₂)₃ H 5′- free COOMe 107 CH H 3-PhOCH₂ H p-tol 108 CH4-NCPhO(CH₂)₃ H H free 109 CH HO H H free 110 CH PhOCH₂ H H free 111 CHPhO(CH₂)₂ H H p-tol 112 CH Ph(CH₂)₃O(CH₂)₂ H H oxal 113 CH 3-Ph(CH₂)₃OPhH H oxal 114 CH PhO(CH₂)₃ H H free 115 CH 2-H₂NCOPhO(CH₂)₃ H H free 116CH 3-H₂NCOPhO(CH₂)₃ H H p-tol 118 CH 4-(3-FPhCH₂O)PhO H 5′-F HCl 119 N4-cOctCH₂OPhCO H H free 120 N 4-[3-FPhCH₂N(Me)]PhCO H H free 121 N4-cHexCH₂N(Me)PhCO H H free 122 N 3-cHexCH₂OPhCO H H HCl 123 N3-cHexCH₂N(Me)PhCO H H HBr 124 N Ph(CH₂)₂CO H H p-tol 125 N PhCO H Hfree 127 N PhOCH₂CO H H p-tol 128 N PhCH₂CO H H p-tol 129 N PhNHCH₂CO HH free 130 N Ph(CH₂)₃CO H H p-tol 132 N PhCONHCH₂CO H H oxal 133 NPhN(Me)CH₂CO H H 2oxal 134 N 4-HepOPhCO H H p-tol 135 N4-(3-NCPhCH₂O)PhCO 2-Me H HCl 136 N 4-(3-NCPhCH₂O)PhCO 3-Me H free 137 N6-(3-ClPhCH₂O)Py3CO H H oxal 138 N 3-(3-ClPhCH₂O)PhCO H H HCl 139 N4-H₂NCOPhOCH₂CO H H free 140 N 2-H₂NCOPhOCH₂CO H H free 141 N3-H₂NCOPhOCH₂CO H H free 142 N PhSO₂ H H free

TABLE 20

Ex No. T R¹ R² R⁴ Sal 143 N PhCH₂SO₂ H H free 144 N PhCH₂O—CO H H p-tol145 N Py3O—CO H H free 146 N PhCH₂NHCO H H free 147 N 4-(3-ClPhCH₂O)PhCOH H free 148 N 4-(3-MePhCH₂O)PhCO H H oxal 149 N 4-(3-F₃CPhCH₂O)PhCO H Hfree 150 N 4-(3-MeOPhCH₂O)PhCO H H oxal 151 N 4-(3-NCPhCH₂O)PhCO H Hfree 152 N 4-(3,5-diFPhCH₂O)PhCO H H free 153 N 4-(3-F₃COPhCH₂O)PhCO H Hfree 154 N 4-(3-O₂NPhCH₂O)PhCO H H free 155 N 4-(4-FPhCH₂O)PhCO H H free156 N 4-(2-FPhCH₂O)PhCO H H free 157 N 4-Py2CH₂OPhCO H H free 158 N4-(1-MeAzep3O)PhCO H H free 159 N 4-(3-BrPhCH₂O)PhCO H H free 160 N4-[3-ClPh(CH₂)₂O]PhCO H H free 161 N 4-(4-NCPhCH₂O)PhCO H H free 162 N4-(3-IPhCH₂O)PhCO H H free 163 N 4-(3-Me₂NPhCH₂O)PhCO H H free 164 N2-Cl-4-(3-NCPhCH₂O)PhCO H H free 165 N 3-Cl-4-(3-NCPhCH₂O)PhCO H H free166 N 4-(3-NCPhCH₂O)-3-MeO-PhCO H H HCl 167 N 4-(3-MeOCOPhCH₂O)PhCO H Hfree 168 CH cHexCH₂NHCO H H free 169 CH MeOCO(CH₂)₃ H H oxal 170 CHH₂NCO(CH₂)₃ H H oxal 171 CH PhCH₂N(Me)CO H H free 172 CH Py3CH₂NHCO H Hfree 173 CH PhNHCO H H free 174 CH Ph(CH₂)₂NHCO H H free 175 CHPh(CH₂)₄NHCO H H free 176 CH 4-OctPhNHCO H H free 177 CH4-H₂NCOPhNHCO(CH₂)₃ H H free 178 CH 3-H₂NCOPhNHCO(CH₂)₃ H H free 179 CH3-H₂NCOCH₂OPh H H HCl

TABLE 21

Ex No. T R¹ R² R⁴ Sal 180 CH 3-(4-H₂NCOPIPE1COCH₂O)Ph H H HCl 181 CH2-H₂NCOPhNHCO(CH₂)₃ H H fum 182 CH 4-BuPhNHCO H H free 183 CH4-BuOPhNHCO H H free 184 CH 4-HexOPh(CH₂)₂NHCO H H free 185 CH4-Ph(CH₂)₄OPh(CH₂)₂NHCO H H free 186 CH 4-cPen(CH₂)₃OPh(CH₂)₂NHCO H Hfree 187 CH 4-HexPhNHCO H H free 188 CH 4-[4-MeOCOPh(CH₂)₂]PhNHCO H Hfree 189 CH 4-HO(CH₂)₂PhNHCO H H free 190 CH 4-PhCH₂OPhNHCO H H free 191CH 2-H₂NCO(CH₂)₂PhNHCO H H free 192 CH 4-Ph-1,3-Thiaz2NHCO H H free 193N PhCH₂OCO 3-COOH H free 194 CH 4-HOOCPhO(CH₂)₂ H H free 195 CH3-HOOCCH₂OPh H H free 196 CH 1-MeBenzIM2 H H free 197 CH Ph(CH₂)₅CONH HH free 198 CH 3-HOPhO H H free 199 CH 4-HOPhO H H free 200 CH3-cHexCH₂OPhO H H HCl 201 CH 3-cHex(CH₂)₂OPhO H H HCl 202 CH3-(3-FPhCH₂O)PhO H H HCl 203 CH 3-(2-FPhCH₂O)PhO H H HCl 204 CH3-(4-FPhCH₂O)PhO H H HCl 205 CH 3-(3-NCPhCH₂O)PhO H H oxal 206 CH4-(3-ClPhCH₂O)PhO H H HCl 207 CH 4-cHex(CH₂)₂OPhO H H HCl 208 CH4-(2-FPhCH₂O)PhO H H HCl 209 CH 4-(4-FPhCH₂O)PhO H H HCl 210 CH4-(3-NCPhCH₂O)PhO H H oxal 211 CH 4-(3-MeOCOPhCH₂O)PhO H H free 212 CH4-(3-H₂NCOPhCH₂O)PhO H H free 213 CH 4-cHex(CH₂)₃OPhO H 5′-COOMe free

TABLE 22

Ex No. T R¹ R² R⁴ Sal 214 CH 4-PIPE1(CH₂)₂OPhO H 5′-COOMe HCl 215 CH4-(3-NCPhCH₂O)PhO H 5′-COOMe oxal 216 CH 4-cHexCH₂OPhO H 5′-COOMe free217 CH 4-HOPhO H 5′-COOH free 218 CH 4-(3-FPhCH₂O)PhO H 5′-COOH free 219CH PhCH₂ H 5′-COOH free 220 CH Ph H 5′-COOH free 221 CH 4-PhCH₂OPhO H5′-COOH free 223 CH PhCO H 5′-COOH free 224 CH PhCH₂O H 5′-COOH free 225CH Ph(CH₂)₂ H 5′-COOH free 226 CH 4-PIPERI1(CH₂)₂OPhO H 5′-COOH free 227CH 4-NCPhO(CH₂)₃ H 5′-COOH free 228 CH 4-cHex(CH₂)₂OPhO H 5′-COOH free229 CH 4-cHex(CH₂)₃OPhO H 5′-COOH free 230 CH 4-(3-NCPhCH₂O)PhO H5′-COOH free 231 N Ph(CH₂)₂ H 5′-COOH 2HCl 232 CH PhCH₂OCH₂ H 5′-COOHfree 233 CH 4-(3-MeOPhCH₂O)PhO H 5′-COOH free 234 CH 3-(3-FPhCH₂O)PhO H5′-COOH free 235 CH 3-(3-NCPhCH₂O)PhO H 5′-COOH free 236 CH4-(3-MeOCOPhCH₂O)PhO H 5′-COOH free 237 CH 4-cHexCH₂OPhO H 5′-COOH free238 CH Ph(CH₂)₃ H 5′-COOH free 239 CH PhO(CH₂)₃ H 5′-COOH free 240 CHPhO(CH₂)₂ H 5′-COOH free 241 CH 4-H₂NCOPh(CH₂)₂ H 5′-COOH free 242 CH3-cHex(CH₂)₂OPhO H 5′-COOH free 243 N Ph(CH₂)₃ H 5′-COONa free 244 CH4-(3-FPhCH₂O)PhO H 5′-CONHCH₂COOH free 245 CH 4-(3-FPhCH₂O)PhO H5′-CONH₂ free 246 CH 4-PhCH₂OPhO H 5′-CONH₂ free 247 CH PhCH₂ H5′-CONHCH₂CONH₂ HCl 248 CH PhCH₂ H 5-(4-H₂NCOPIPERI1CO)- HCl

TABLE 23

Ex No. T R¹ R² R⁴ Sal 249 CH 4-(3-FPhCH₂O)PhO H 5′-CONHCH₂CONH₂ HCl 250CH 4-(3-FPhCH₂O)PhO H 5′-Mo4(CH₂)₂NHCO- oxal 251 CH 4-(3-FPhCH₂O)PhO H5′-CONH(CH₂)₂OMe oxal 252 CH 4-(3-FPhCH₂O)PhO H 5′-(4-H₂NCOPIPE1CO)-free 253 CH 4-(3-FPhCH₂O)PhO H 5′-CONH(CH₂)₂CONH₂ HCl 254 CH4-(3-FPhCH₂O)PhO H 5′-PIPE1(CH₂)₂NHCO- 2HCl 255 CH 4-(3-EPhCH₂O)PhO H5′-CONH(CH₂)₂OH HCl 256 CH 4-(3-FPhCH₂O)PhO H 5′-(4-HOPh(CH₂)₂NHCO)-free 257 CH 4-(3-FPhCH₂O)PhO H 5′-(4-MePIPERA1CO)- oxal 258 CH PhCH₂ H5′-(3-H₂NCOPh)- free 259 CH PhCH₂ H 5′-Py3 free 260 CH 4-(3-FPhCH₂O)PhOH 5′-NH₂ HCl 261 CH 4-(3-FPhCH₂O)PhO H 5′-(4-HOOCPIPE1)- oxal 262 CH4-(3-FPhCH₂O)PhO H 5′-CH₂OCH₂COOH free 263 CH 4-(3-FPhCH₂O)PhO H5′-CH₂OH free

TABLE 24 Ex No. Str Sal 022

free 032

2HCl 038

free 065

free 104

fum 117

free 126

p-tol 131

p-tol 222

free 264

free

TABLE 25

Ex No. T R¹ R⁴ Sal 265 CH Ph(CH₂)₂ 5′-(4-MeOCOPh)- free 266 CH Ph(CH₂)₂5′-(3-H₂NCOPh)- free 267 CH 3-NCPh(CH₂)₂ 5′-COOH free 268 CH

H free 269 CH

H free 270 CH Ph(CH₂)₂ 5′-Br free 271 CH cHex(CH₂)₂ H free 272 CHcHex(CH₂)₂ 5′-COOMe free 273 CH

5′-COOH free 274 CH 3-ClPh(CH₂)₂ 5′-COOH free 275 CH 4-NCPh(CH₂)₂5′-COOH free 276 CH 3-MeOPh(CH₂)₂ 5′-COOH free 277 CH 3-FPh(CH₂)₂5′-COOH free 278 CH 2-NCPh(CH₂)₂ 5′-COOH free 279 CH 3-H₂NCOPh(CH₂)₂5′-COOH free 280 CH 3-Me₂NCOPh(CH₂)₂ 5′-COOH free 281 CH BIP4(CH₂)₂5′-COOH Na 282 CH 4-FPh(CH₂)₂ 5′-COOH free 283 CH 2-ClPh(CH₂)₂ 5′-COOHfree 284 CH 4-ClPh(CH₂)₂ 5′-COOH free 285 CH 4-BrPh(CH₂)₂ 5′-COOH free

TABLE 26

Ex No. T R¹ R⁴ Sal 286 CH 4-MeOPh(CH₂)₂ 5′-COOH free 287 CH Ph(CH₂)₄5′-COOH free 288 CH 2-FPh(CH₂)₂ 5′-COOH free 289 CH cHex(CH₂)₂ 5′-COOHfree 290 CH 4-Py2Ph(CH₂)₂ 5′-COOH free 291 CH Ph(CH₂)₂

free 292 CH 3-BrPh(CH₂)₂ 5′-COOH free 293 CH BIP3(CH₂)₂ 5′-COOH free 294CH 3-NCBIP3(CH₂)₂ 5′-COOH free 295 CH Py4Ph(CH₂)₂ 5′-COOH free 296 CHPy3Ph(CH₂)₂ 5′-COOH free 297 CH Py2(CH₂)₂ 5′-COOH free 298 CH3-Py2Ph(CH₂)₂ 5′-COOH Na 299 CH 4′-FBIP4(CH₂)₂ 5′-COOH free 300 CH4′-MeOBIP4(CH₂)₂ 5′-COOH free 301 CH 4′-NCBIP4(CH₂)₂ 5′-COOH free 302 CH3′-FBIP4(CH₂)₂ 5′-COOH free 303 CH 3′-MeOBIP4(CH₂)₂ 5′-COOH free 304 CH2′-FBIP4(CH₂)₂ 5′-COOH free 305 CH 3-cHexNHCOPh(CH₂)₂ 5′-COOH Na 306 CH3-PIPE1COPh(CH₂)₂ 5′-COOH Na 307 CH 3-M o4COPh(CH₂)₂ 5′-COOH Na 308 CH4-PIPE1COPh(CH₂)₂ 5′-COOH Na 309 CH 4-M o4COPh(CH₂)₂ 5′-COOH Na 310 CH3-PYRR1COPh(CH₂)₂ 5′-COOH Na 311 CH 3-(4-Py2PIPERA1CO)Ph(CH₂)₂ 5′-COOHfree

TABLE 27

Ex No. T R¹ R⁴ Sal 312 CH 4-Et₂NCOPh(CH₂)₂ 5′-COOH free 313 CH1-(6-MePy2)PIPE4(CH₂)₃ 5′-COOH Na 314 CH 1-ISOQUI1PIPE4(CH₂)₃ 5′-COOH Na315 CH 1-QUI2PIPE4(CH₂)₃ 5′-COOH Na 316 CH 4- 5′-COOH NaISOQUI1PIPERA1(CH₂)₃ 317 CH 1-NAPH1PIPE4(CH₂)₃ 5′-COOH Na 318 CH3-NCPh(CH₂)₂ 5′-CONH₂ free 319 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 320 CHPh(CH₂)₂ 5′-CONH₂ free 321 CH 3-MeOPh(CH₂)₂ 5′-CONH₂ free 322 CH3-FPh(CH₂)₂ 5′-CONH₂ free 323 CH 2-NCPh(CH₂)₂ 5′-CONH₂ free 324 CH3-H₂NCOPh(CH₂)₂ 5′-CONH₂ free 325 CH 3-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 326CH cHex(CH₂)₂ 5′-CONH₂ free 327 CH 3-ClPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 328CH 3-MeOPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 329 CH 3-FPh(CH₂)₂ 5′-CONH(CH₂)₂OHoxal 330 CH 3-NCPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 331 CH 2-NCPh(CH₂)₂5′-CONH(CH₂)₂OH oxal 332 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂SO₃H HCl 333 CHPh(CH₂)₂ 5′-CONH(CH₂)₂CONH₂ free 334 CH 2-FPh(CH₂)₂ 5′-CONH₂ free 335 CHPh(CH₂)₂

free 336 CH Py4(CH₂)₂ 5′-CONH₂ free

TABLE 28

Ex No. T R¹ R⁴ Sal 337 CH Py3(CH₂)₂ 5′-CONH₂ free 338 CH 4′-FBIP4(CH₂)₂5′-CONH₂ free 339 CH 4′-MeOBIP4(CH₂)₂ 5′-CONH₂ free 340 CH BIP3(CH₂)₂5′-CONH₂ free 341 CH 3′-NCBIP3(CH₂)₂ 5′-CONH₂ free 342 CH Ph(CH₂)₂5′-CONH(CH₂)₃OH oxal 343 CH Ph(CH₂)₂ 5′-CONH(CH₂)₃NMe₂ oxal 344 CH4′-NCBIP4(CH₂)₂ 5′-CONH₂ free 345 CH 3′-FBIP4(CH₂)₂ 5′-CONH₂ free 346 CH2′-FBIP4(CH₂)₂ 5′-CONH₂ free 347 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂Py4 oxal 348CH Ph(CH₂)₂ 5′-CONH(CH₂)₂Py3 oxal 349 CH 3-Py2Ph(CH₂)₂ 5′-CONH₂ free 350CH 2-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 351 CH 3-cHexNHCOPh(CH₂)₂ 5′-CONH₂free 352 CH 3-MeNHCOPh(CH₂)₂ 5′-CONH₂ free 353 CH 4-H₂NCOPh(CH₂)₂5′-CONH₂ free 354 CH 4-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 355 CH3-PIPE1COPh(CH₂)₂ 5′-CONH₂ free 356 CH 3-Mo4COPh(CH₂)₂ 5′-CONH₂ free 357CH 4-PIPE1COPh(CH₂)₂ 5′-CONH₂ free 358 CH 4-Mo4COPh(CH₂)₂ 5′-CONH₂ free359 CH 3-PYRR1COPh(CH₂)₂ 5′-CONH₂ free 360 CH 3-Et₂NCOPh(CH₂)₂ 5′-CONH₂free 361 CH

5′-CONH₂ free

TABLE 29

Ex No. T R¹ R⁴ Sal 362 CH 4-Et₂NCOPh(CH₂)₂ 5′-CONH₂ free 363 CH4-PYRR1COPh(CH₂)₂ 5′-CONH₂ free 364 CH

5′-CONH₂ free 365 CH 3-(4-Py2PIPERA1CO) Ph(CH₂)₂ 5′-CONH₂ free 366 CH3-(4-PhPIPERA1CO) Ph(CH₂)₂ 5′-CONH₂ free 367 CH 4-(4-Py2PIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 368 CH 4-(4-PhPIPERA1CO) Ph(CH₂)₂ 5′-CONH₂ free369 CH 3-FCH₂CH₂NHCOPh(CH₂)₂ 5′-CONH₂ HCl 370 CH 3-HO(CH₂)₂NHCOPh(CH₂)₂5′-CONH₂ free 371 CH 3-tBuNHCOPh(CH₂)₂ 5′-CONH₂ free 372 CH3-iPrNHCOPh(CH₂)₂ 5′-CONH₂ free 373 CH 4-(2,2-DIFPYRR1CO)Ph(CH₂)₂5′-CONH₂ free 374 CH 3-H₂NCONHPh(CH₂)₂ 5′-CONH₂ free 375 CH3-PYRR1CONHPh(CH₂)₂ 5′-CONH₂ free 376 CH 3-(2,2-DIFPYRR1CO)Ph(CH₂)₂5′-CONH₂ free 377 CH 3-(4-NAPH1PIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 378 CH1-(6-MePy2)PIPE4(CH₂)₃ 5′-CONH₂ free 379 CH 1-ISOQUI1PIPE4(CH₂)₃5′-CONH₂ free 380 CH 1-QUI2PIPE4(CH₂)₃ 5′-CONH₂ free 381 CH4-ISOQUI1PIPERA1(CH₂)₃ 5′-CONH₂ free 382 CH 1-NAPH1PIPE4(CH₂)₃ 5′-CONH₂free

TABLE 30

Ex No. R¹ R⁴ Sal 383 3-HepOPhNHCO H free 384 4-HepOPhNHCO H free 385Py2NHCO(CH₂)₃ H 2HCl 386 4-OctPhNHCO(CH₂)₃ H oxal 387 Ph□CH₂□₄NHCO(CH₂)₃H oxal 388 4-HexPhNHCO CONH₂ free 389 4-(3-FPhCH₂O)PhO OAc oxal 3904-(3-FPhCH₂O)PhO OH free 391 4-(3-FPhCH₂O)PhO CN free 3924-cHex(CH₂)₄OPhO H free 393

CO₂H free 394

CO₂H free 395 4-cPen(CH₂)₂OPhO CO₂H free 396 4-(3-FPhCH₂O)PhOCH₂ H free

TABLE 31

Ex No. R¹ R⁴ Sal 397

CONH₂ free 398

CONH₂ free 399 Ph(CH₂)₂

free 400 4-(3-FPhCH₂O)PhCH₂ H HCl 401 4-(3-FPhCH₂O)PhCH₂ CO₂H free 402Ph(CH₂)₂ OH free 403

CO₂H free 404

CONH₂ free 405 4-NAPH1PIPERA1(CH₂)₃ CO₂H Na 406 1-(6-MePy2)PIPE4(CH₂)₂CO₂H Na 407 1-(6-MePy2)PIPE4(CH₂)₂ CONH₂ free 408 4-NAPH1PIPERA1(CH₂)₃CONH₂ free

TABLE 32

Ex No. R¹ R⁴ Sal 409 Ph(CH₂)₃ CONH₂ free 410 Ph CONH₂ free 411 Ph(CH₂)₅CONH(CH₂)₂OH 2HCl 412 Ph(CH₂)₅ CONH₂ free 413 4-(3-FPhCH₂O)PhCH₂ H 2HCl414 BIP4(CH₂)₂ CO₂H Na 415 BIP4(CH₂)₂ CONH₂ free

TABLE 33 Ex No. Str Sal 416

p-tol 417

free 418

free 419

p-tol 420

oxal 421

free 422

HCl 423

free

TABLE 34

Ex No. T R¹ Sal 424 CH Ph(CH₂)₂ free 425 N Ph(CH₂)₂ free 426 CH Ph(CH₂)₃free 427 CH 4-H₂NCOPh(CH₂)₂ free 428 CH 3-cHex(CH₂)₂OPhO free 429 NPh(CH₂)₃ free 430 CH 4-cHex(CH₂)₂OPhO free 431 CH 4-(3-MeOPhCH₂O)PhOfree 432 CH 4-(3-MeOCOPhO)PhO free 433 CH 3-PYRR1COPh(CH₂)₂ free 434 CH3-PIPE1COPh(CH₂)₂ free 435 CH

free 436 CH 3-H₂NCONHPh(CH₂)₂ free 437 CH 3-PIPE1CONHPh(CH₂)₂ free

TABLE 35 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 001 207 (M + H)⁺FAB002 1.59-1.74 (2H, br), 1.90-2.05 (2H, br), 3.33-3.45 (1H, br),3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.45-4.55(1H, m), 5.07 (2H, s), 6.97 (4H, s), 7.15 (1H, dt, J = 2.4, 8.1 Hz),7.24-7.30 (2H, m), 7.40-7.47 (2H, m), 7.64-7.66 (1H, m), 8.41-8.45 (2H,m), DMSO: 423 (M + H)⁺FAB 003 1.40-1.70 (2H, m), 1.85 (2H, d, J = 12.7Hz), 3.10 (1H, t, J = 12.7 Hz) 3.25 (1H, t, J = 12.2 Hz), 3.65-3.75 (1H,m), 4.06 (1H, d, J = 12.2 Hz), 4.23 (1H, d, J = 12.7 Hz), 5.26 (2H, s),7.14-7.22 (3H, m), 7.29-7.34 (2H, m), 7.42-7.50 (2H, m), 7.64-7.67 (1H,m), 8.03 (2H, d, J = 9.3 Hz), 8.44-8.45 (2H, m), DMSO: 435 (M + H)⁺FAB004 436 (M + H)⁺FAB 005 424 (M + H)⁺FAB 006 438 (M + H)⁺FAB 007 438 (M +H)⁺FAB 008 418 (M + H)⁺FAB 009 411 (M + H)⁺FAB 010 1.10-1.30 (2H, br),1.64 (2H, d, J = 12.7 Hz), 1.71-1.82 (1H, m), 2.56 (2H, d, J = 7.4 Hz),2.83 (1H, t, J = 11.8 Hz), 2.99 (1H, t, J = 11.8 Hz), 4.00 (1H, d, J =11.8 Hz), 4.15 (1H, d, J = 11.8 Hz), 7.16-7.23 (3H, m), 7.26-7.32 (2H,m), 7.44 (1H, dd, J = 4.4, 8.3 Hz), 7.59-7.64 (1H, m), 8.40 (1H, d, J =2.0 Hz), 8.43 (1H, d, J = 4.4 Hz), DMSO: 297 (M + H)⁺FAB 011 1.59-1.75(2H, br), 1.90-2.06 (2H, br), 3.33-3.43 (1H, br), 3.45-3.55 (1H, br),3.65-3.79 (1H, br), 3.83-3.94 (1H, br), 4.60-4.69 (1H, m), 5.09 (2H, s),6.57-6.66 (3H, m), 7.19 (1H, t, J = 8.3 Hz), 7.30-7.47 (6H, m),7.62-7.66 (1H, m), 8.41-8.45 (2H, m), DMSO: 405 (M + H)⁺FAB 0121.59-1.74 (2H, br), 1.90-2.05 (2H, br), 3.33-3.43 (1H, br), 3.45-3.55(1H, br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.47-4.55 (1H, m),5.04 (2H, s), 6.95 (4H, s), 7.30-7.46 (6H, m), 7.61-7.66 (1H, m),8.41-8.45 (2H, m), DMSO: 405 (M + H)⁺FAB 013 1.59-1.76 (2H, br),1.90-2.05 (2H, br), 2.69 (3H, s), 3.33-3.45 (1H, br), 3.45-3.60 (1H,br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.48-4.57 (1H, m), 5.07(2H, s), 6.97 (4H, s), 7.15 (1H, dt, J = 2.4, 8.3 Hz), 7.24-7.30 (2H,m), 7.40-7.47 (2H, m), 7.81 (1H, d, J = 8.7 Hz), 8.19 (1H, dd, J = 2.5,8.3 Hz), 8.74 (1H, d, J = 2.4 Hz), DMSO: 437 (M + H)⁺FAB 014 1.50-1.70(2H, br), 1.89 (2H, d, J = 12.7 Hz), 3.11 (1H, t, J = 11.7 Hz), 3.27(1H, t, J = 11.7 Hz), 3.75 (1H, tt, J = 3.2, 11.3 Hz), 4.07 (1H, d, J =11.7 Hz), 4.23 (1H, d, J = 11.7 Hz), 7.45 (1H, dd, J = 5.4, 8.3 Hz),7.57 (2H, t, J = 7.8 Hz), 7.63-7.69 (2H, m), 8.03 (2H, dd, J = 1.4, 8.3Hz), 8.44 (2H, dd, J = 1.4, 4.9 Hz), DMSO: 311 (M + H)⁺FAB

TABLE 36 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 015 1.55-1.75 (2H,br), 1.83 (2H, d, J = 12.2 Hz), 2.81 (1H, tt, J = 3.4, 12.2 Hz), 4.15(1H, d, J = 12.2 Hz), 4.31 (1H, d, J = 12.2 Hz), 7.10-7.17 (2H, m),7.31-7.37 (2H, m), 7.44-7.48 (1H, m), 7.63-7.67 (1H, m), 8.43-8.46 (2H,m), DMSO: 301 (M + H)⁺FAB 016 326 (M + H)⁺FAB 017 2.46-2.62 (6H, m),2.72-2.80 (2H, m), 3.40-3.50 (2H, br), 3.57-3.65 (2H, br), 7.16-7.32(5H, m), 7.45 (1H, dd, J = 4.6, 8.3), 7.61-7.65 (1H, m), 8.42-8.45 (2H,m), DMSO: 312 (M + H)⁺FAB 018 1.60-1.75 (2H, br), 1.95-2.10 (2H, br),3.33-3.41 (1H, br), 3.47-3.56 (1H, br), 3.69-3.78 (1H, br), 3.84-4.03(1H, br), 5.96 (2H, s), 6.46 (1H, dd, J = 2.4, 8.7 Hz), 6.73 (1H, d, J =2.4 Hz), 6.82 (1H, d, J = 8.7 Hz), 7.74-7.78 (1H, m), 8.04 (1H, d, J =8.3 Hz), 8.62 (1H, d, J = 4.9 Hz), 8.72 (1H, s), DMSO: 343 (M + H)⁺FAB019 1.20-1.40 (2H, br), 1.79-1.89 (2H, br), 1.94-2.04 (1H, m), 2.94 (1H,t, J = 11.8 Hz), 3.07 (1H, t, J = 11.8 Hz), 3.80 (2H, d, J = 6.3 Hz),4.05 (1H, d, J = 11.8 Hz), 4.22 (1H, d, J = 11.8 Hz), 5.95 (2H, s), 6.37(1H, dd, J = 2.5, 8.3 Hz), 6.64 (1H, d, J = 2.5 Hz), 6.80 (1H, d, J =8.3 Hz), 7.45 (1H, dd, J = 4.9, 8.3 Hz), 7.630 (1H, d, J = 8.3 Hz),8.40-8.45 (2H, m), DMSO: 357 (M + H)⁺FAB 020 1.16-1.32 (2H, br),1.64-1.82 (3H, m), 2.92 (1H, t, J = 11.7 Hz), 3.06 (1H, t, J = 11.7 Hz),3.96 (2H, t, J = 6.4 Hz), 4.01 (1H, d, J = 11.7 Hz), 4.17 (1H, d, J =11.7 Hz), 5.95 (2H, s), 6.37 (1H, dd, J = 2.5, 8.3 Hz), 6.63 (1H, d, J =2.5 Hz), 6.80 (1H, d, J = 8.3 Hz), 7.74-7.80 (1H, m), 8.02-8.07 (1H, m),8.61 (1H, d, J = 5.4 Hz), 8.71 (1H, brs), DMSO: 371 (M + H)⁺FAB 0211.63-1.80 (2H, br), 1.97-1.99 (2H, br), 3.35-3.45 (1H, br), 3.50-3.60(1H, br), 3.71-3.79 (1H, br), 3.86-3.95 (1H, br), 4.63-4.70 (1H, m),6.94 (1H, t, J = 7.3 Hz), 7.01 (2H, d, J = 8.3 Hz), 7.30 (2H, t, J = 7.3Hz), 7.76 (1H, dd, J = 4.8, 8.3 Hz), 8.05 (1H, d, J = 8.3 Hz), 8.62 (1H,d, J = 4.8 Hz), 8.73 (1H, s), DMSO: 299 (M + H)⁺FAB 022 2.85-2.98 (2H,m), 3.68 (1H, t, J = 4.9 Hz), 3.84 (1H, t, J = 5.8 Hz), 4.62 (1H, s),4.82 (1H, s), 7.20-7.28 (4H, m), 7.46 (1H, dd, J = 4.4, 8.3 Hz),7.65-7.69 (1H, m), 8.44-8.47 (2H, m), DMSO: 255 (M + H)⁺FAB 0233.20-3.24 (4H, br), 3.55-3.65 (2H, br), 3.72-3.80 (2H, br), 6.83 (1H, t,J = 7.1), 7.00 (2H, d, J = 8.3), 7.25 (2H, t, J = 7.3), 7.46 (1H, dd, J= 4.4, 8.3), 7.63-7.69 (1H, m), 8.43-8.46 (2H, m), DMSO: 284 (M + H)⁺FAB024 1.61-1.80 (2H, m), 1.97-2.12 (2H, m), 3.28-3.62 (2H, m), 3.68-3.99(2H, m), 4.71-4.80 (1H, m), 7.05 (2H, d, J = 8.8 Hz), 7.12-7.22 (1H, m),7.45 (1H, dd, J = 4.9 Hz, 8.3 Hz), 7.61-7.68 (1H, m), 7.78-7.88 (3H, m),8.41-8.46 (2H, m), DMSO: 342 (M + H)⁺FAB 025 356 (M + H)⁺FAB 026 370(M + H)⁺FAB 027 342 (M + H)⁺FAB

TABLE 37 Ex. DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 028 356 (M + H)⁺FAB029 481 (M + H)⁺FAB 030 1.60-1.78 (2H, m), 1.93-2.06 (2H, m), 3.04 (6H,s), 3.30-3.93 (4H, m), 4.49-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s),7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.52 (2H, m), 8.05-8.08 (2H,m), DMSO: 466 (M + H)⁺FAB 031 424 (M + H)⁺FAB 032 2.04-2.20 (1H, m),2.40-2.60 (1H, m), 3.10-4.10 (8H, m), 4.32-4.44 (2H, m), 7.41-7.50 (3H,m), 7.66-7.82 (2H, m), 8.05-8.16 (1H, m), 8.62 (1H, br), 8.80 (1H, d, J= 12.7 Hz), 11.58 (1H, br), DMSO: 312 (M + H)⁺FAB 033 1.25-1.35 (2H, m),1.55-1.66 (2H, m), 1.70-1.83 (2H, m), 2.60 (2H, t, J = 7.3 Hz),3.00-3.22 (4H, m), 3.40-3.70 (4H, m), 4.00-4.35 (2H, m), 7.15-7.33 (5H,m), 7.62 (1H, br), 7.85 (1H, br), 8.50-8.65 (2H, m), 10.90-11.40 (1H,br), DMSO: 354 (M + H)⁺FAB 034 3.09 (4H, br), 3.50-3.80 (4H, m), 5.04(2H, s), 6.94 (4H, d, J = 1.7 Hz), 7.30-7.49 (6H, m), 7.63-7.68 (1H, m),8.43-8.46 (2H, m), DMSO: 390 (M + H)⁺FAB 035 1.10-1.32 (2H, m),1.46-1.60 (3H, m), 1.80 (2H, d, J = 11.7 Hz), 2.62 (2H, t, J = 7.8 Hz),2.88 (1H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 4.17 (1H, t, J =12.2 Hz), 7.16-7.23 (3H, m), 7.27-7.31 (2H, m), 7.89 (1H, dd, J = 5.3,8.8 Hz), 8.18-8.22 (1H, m), 8.69 (1H, dd, J = 1.0, 5.3 Hz), 8.82 (1H, d,J = 2.5 Hz), DMSO: 311 (M + H)⁺FAB 036 1.52-1.68 (2H, br), 1.88-2.01(2H, br), 3.22-3.33 (1H, br), 3.37-3.48 (1H, br), 3.65-3.75 (2H, m),3.82-3.91 (1H, br), 4.56 (2H, s), 7.26-7.32 (1H, m), 7.36 (4H, d, J =4.4 Hz), 7.70 (1H, dd, J = 4.9, 8.3 Hz), 7.95 (1H, dd, J = 1.0, 8.3 Hz),8.58 (1H, d, J = 4.9 Hz), 8.66 (1H, s), DMSO: 313 (M + H)⁺FAB 037 1.69(2H, d, J = 12.7 Hz), 1.91-2.11 (2H, m), 3.33 (1H, t, J = 12.7 Hz), 3.47(1H, t, J = 12.7 Hz), 3.93-4.07 (2H, m), 4.13 (1H, d, J = 12.7 Hz), 7.23(1H, t, J = 7.4 Hz), 7.35 (2H, t, J = 7.4 Hz), 7.52-7.55 (2H, m), 7.81(1H, dd, J = 5.4, 8.3 Hz), 8.10-8.14 (1H, m), 8.63 (1H, d, J = 4.9 Hz),8.77 (1H, d, J = 2.4 Hz), DMSO: 299 (M + H)⁺FAB 038 2.58 (1H, br), 2.64(1H, br), 3.67 (1H, br), 3.83 (1H, br), 4.13 (1H, s), 4.32 (1H, s), 6.21(1H, s), 7.29 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.44-7.50(3H, m), 7.67 (1H, d, J = 8.3 Hz), 8.44-8.47 (2H, m), DMSO: 281 (M +H)⁺FAB 039 1.95 (3H, s), 2.00-2.16 (2H, br), 2.39-2.47 (2H, br),3.20-3.30 (1H, br), 3.35-3.45 (1H, br), 3.63-3.73 (1H, br), 3.79-3.89(1H, br), 7.29-7.34 (1H, m), 7.37-7.46 (5H, m), 7.60-7.64 (1H, m),8.40-8.43 (2H, m), DMSO: 325 (M + H)⁺FAB

TABLE 38 Ex. DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 040 1.61-1.81 (2H,m), 1.83 (2H, d, J = 12.2 Hz), 2.77-2.87 (1H, m), 3.05 (1H, t, J = 12.2Hz), 3.19 (1H, t, J = 12.2 Hz), 4.16 (1H, d, J = 12.2 Hz), 4.33 (1H, d,J = 12.2 Hz), 7.19-7.24 (1H, m), 7.27-7.36 (5H, m), 7.91 (1H, dd, J =5.3, 8.3 Hz), 7.36 (1H, d, J = 8.3 Hz), 8.70 (1H, d, J = 4.9 Hz), 8.85(1H, s), DMSO: 283 (M + H)⁺FAB 041 35 (M + H)⁺FAB 042 1.60-1.76 (2H, m),1.92-2.05 (2H, m), 3.30-3.92 (4H, m), 4.48-4.55 (1H, m), 5.07 (2H, s),6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m), 7.39-7.48 (1H, m),7.93-7.96 (1H, m), 8.44 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 2.0 Hz),DMSO: 457 (M + H)⁺FAB 043 1.14-1.35 (2H, m), 1.68-1.84 (5H, m), 2.89(1H, t, J = 11.7 Hz), 3.05 (1H, t, J = 11.7 Hz), 3.96-4.21 (4H, m), 6.98(2H, d, J = 8.8 Hz), 7.16 (1H, brs), 7.44 (1H, dd, J = 4.9, 8.3 Hz),7.60-7.65 (1H, m), 7.76-7.87 (3H, m), 8.40-8.44 (2H, m), DMSO: 370 (M +H)⁺FAB 044 1.60-1.75 (2H, m), 1.92-2.05 (2H, m), 3.30-3.92 (4H, m),4.46-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m),7.24-7.29 (2H, m), 7.40-7.47 (1H, m), 8.06-8.086 (1H, m), 8.47 (1H, d, J= 2.0 Hz), 8.59 (1H, d, J = 2.0 Hz), DMSO: 501 (M⁺)FAB 045 1.60-1.78(2H, m), 1.93-2.06 (2H, m), 3.31-3.57 (6H, m), 3.70-3.93 (6H, m),4.49-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.12-7.17 (1H, m),7.24-7.30 (2H, m), 7.41-7.47 (1H, m), 7.78 (1H, s), 8.19-8.22 (1H, m),8.30-8.33 (1H, m), DMSO: 508 (M + H)⁺FAB 046 1.51-1.70 (2H, m),1.87-2.02 (2H, m), 3.20-3.31 (1H, m), 3.36-3.47 (1H, m), 3.62-3.72 (1H,m), 3.66-3.77 (1H, m), 3.80-3.93 (1H, m), 4.61 (2H, s), 7.33 (1H, br s),7.42 (2H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 8.3, 4.4 Hz), 7.63 (1H, ddd,J = 8.3, 2.4, 1.5 Hz), 7.86 (2H, d, J = 8.3 Hz), 7.94 (1H, br s), 8.42(1H, s), 8.43 (1H, dd, J = 6.3, 1.5 Hz), DMSO: 356 (M + H)⁺FAB 047 340(M + H)⁺FAB 048 390 (M + H)⁺FAB 049 1.40-1.52 (2H, m), 1.55-1.65 (2H,m), 2.30-2.45 (4H, m), 2.60 (2H, t, J = 7.6 Hz), 3.38-3.64 (4H, m),7.12-7.22 (3H, m), 7.25-7.31 (2H, m), 7.44 (1H, dd, J = 4.8, 7.5 Hz),7.60-7.65 (1H, m), 8.40-8.45 (2H, m), DMSO: 340 (M + H)⁺FAB 050 308 (M +H)⁺FAB 051 1.60-1.84 (2H, br), 1.92-2.06 (2H, br), 3.40-3.52 (1H, br),3.55-3.75 (2H, br), 3.79-3.91 (1H, br), 4.59-4.65 (1H, m), 5.08 (2H, s),6.97 (1H, dd, J = 2.9, 9.3 Hz), 7.15 (1H, d, J = 2.9 Hz), 7.22 (1H, d, J= 8.8 Hz), 7.31-7.47 (5H, m), 7.88 (1H, dd, J = 5.4, 8.8 Hz), 8.20 (1H,d, J = 8.3 Hz), 8.68 (1H, d, J = 5.4 Hz), 8.83 (1H, d, J = 1.9 Hz),DMSO: 439 (M + H)⁺FAB

TABLE 39 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 052 311 (M + H)⁺FAB053 1.07-1.27 (2H, m), 1.53 (2H, q, J = 6.4 Hz), 1.62-1.76 (3H, m), 2.90(1H, t, J = 13.2 Hz), 3.04 (1H, t, J = 13.2 Hz), 3.50 (2H, t, J = 6.4Hz), 3.99 (1H, d, J = 13.2 Hz), 4.15 (1H, d, J = 13.2 Hz), 4.46 (2H, s),7.26-7.39 (5H, m), 7.73-7.78 (1H, m), 8.03 (1H, d, J = 8.3 Hz), 8.62(1H, d, J = 4.4 Hz), 8.70 (1H, s), DMSO: 341 (M + H)⁺FAB 054 374, 376(M + H)⁺FAB 055 1.10-1.30 (2H, m), 1.64 (2H, d, J = 13.2 Hz), 1.71-1.83(1H, m), 2.56 (2H, d, J = 7.4 Hz), 2.83 (1H, t, J = 12.2 Hz), 2.98 (1H,t, J = 12.2 Hz), 3.36 (3H, s), 3.99 (1H, d, J = 12.2 Hz), 4.15 (1H, d, J= 12.2 Hz), 4.65 (2H, s), 7.17-7.22 (3H, m), 7.27-7.32 (2H, m), 7.43(1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 2.5, 8.8 Hz), 8.33 (1H, d, J =2.5 Hz), DMSO: 341 (M + H)⁺FAB 056 523 (M + H)⁺FAB 057 342 (M + H)⁺FAB058 471 (M + H)⁺FAB 059 389 (M + H)⁺FAB 060 299 (M + H)⁺FAB 0611.58-1.75 (2H, m), 1.90-2.04 (2H, m), 2.69 (2H, t, J = 7.8 Hz), 2.89(2H, t, J = 7.8 Hz), 3.30-3.91 (7H, m), 4.47-4.55 (1H, m), 5.07 (2H, s),6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m), 7.39-7.47 (1H, m),7.51-7.55 (1H, m), 8.24-8.27 (1H, m), 8.30-8.34 (1H, m), DMSO: 509 (M +H)⁺FAB 062 356 (M + H) + FAB 063 1.07-1.31 (2H, m), 1.42-1.55 (1H, m),1.52-1.64 (2H, m), 1.72-1.86 (2H, m), 2.68 (2H, t, J = 7.5 Hz),2.78-2.91 (1H, m), 2.94-3.07 (1H, m), 3.93-4.07 (1H, m), 4.09-4.23 (1H,m), 7.26 (1H, br s), 7.29 (2H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6,4.8 Hz), 7.61 (1H, ddd, J = 8.6, 2.7, 1.5 Hz), 7.80 (2H, d, J = 8.0 Hz),7.89 (1H, br s), 8.41 (1H, d, J = 2.7 Hz), 8.42 (1H, dd, J = 4.8, 1.1Hz), DMSO: 354 (M + H)⁺FAB 064 354 (M + H)⁺FAB 065 1.34-1.57 (2H, m),1.78-1.90 (2H, m), 2.40-2.48 (1H, m), 2.92-3.08 (1H, m), 3.07-3.23 (1H,m), 3.98-4.13 (1H, m), 4.14-4.28 (1H, m), 6.44 (1H, dd, J = 16.1, 5.9Hz), 6.50 (1H, d, J = 16.1 Hz), 7.30 (1H, br s), 7.45 (1H, dd, J = 8.3,4.4 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.63 (1H, ddd, J = 8.3, 2.5, 1.5 Hz),7.83 (2H, d, J = 8.3 Hz), 7.92 (1H, br s), 8.43 (1H, d, J = 1.9 Hz),8.43 (1H, dd, J = 4.4, 1.9 Hz), DMSO: 352 (M + H)⁺FAB 066 1.03-1.23 (2H,m), 1.35-1.43 (2H, m), 1.46-1.62 (1H, m), 1.72-1.87 (4H, m), 2.82-2.92(3H, m), 3.03 (1H, t, J = 11.8 Hz), 3.74 (3H, s), 4.01 (1H, d, J = 11.8Hz), 4.17 (1H, d, J = 11.8 Hz), 7.11-7.21 (2H, m), 7.42-7.49 (2H, m),7.52-7.56 (1H, m), 7.59-7.63 (1H, m), 8.40-8.44 (2H, m), DMSO: 379 (M +H)⁺ESI

TABLE 40 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 067 308 (M + H)⁺FAB068 339 (M + H)⁺FAB 069 1.04-1.26 (2H, m), 1.35-1.45 (2H, m), 1.48-1.61(1H, m), 1.70-1.83 (4H, m), 2.80-2.94 (1H, m), 2.94-3.10 (1H, m),3.96-4.06 (1H, m), 4.03 (2H, t, J = 6.4 Hz), 4.12-4.22 (1H, m), 6.96(2H, d, J = 8.8 Hz), 7.15 (1H, br s), 7.44 (1H, dd, J = 8.3, 4.9 Hz),7.61 (1H, ddd, J = 8.3, 2.9, 1.5 Hz), 7.81 (1H, br s), 7.83 (2H, d, J =8.8 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.42 (1H, dd, J = 4.9, 1.4 Hz), DMSO:384 (M + H)⁺FAB 070 1.57-1.75 (2H, br), 1.90-2.06 (2H, br), 3.30-3.42(1H, br), 3.45-3.56 (1H, br), 3.65-3.78 (1H, br), 3.80-3.95 (1H, br),4.55-4.61 (1H, m), 5.14 (2H, s), 6.95 (1H, dd, J = 2.9, 9.3 Hz),7.14-7.18 (2H, m), 7.31-7.48 (6H, m), 7.62-7.67 (1H, m), 8.42-8.45 (2H,m), DMSO: 439 (M + H)⁺FAB 071 486 (M + H)⁺FAB 072 385 (M + H)⁺FAB 073578 (M + H)⁺FAB 074 313 (M + H)⁺FAB 075 441 (M + H)⁺FAB 076 439 (M +H)⁺FAB 077 1.21 (3H, t, J = 7.4 Hz), 1.58-1.78 (2H, m), 1.83 (2H, d, J =12.7 Hz), 2.77 (1H, tt, J = 3.8, 12.2 Hz), 2.98 (1H, t, J = 12.2 Hz),3.14 (1H, t, J = 12.2 Hz), 4.10-4.21 (3H, m), 4.31 (1H, d, J = 12.2 Hz),4.76 (2H, s), 6.76 (1H, dd, J = 2.0, 7.4 Hz), 6.87 (1H, t, J = 2.0 Hz),6.90 (1H, d, J = 7.4 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.46 (1H, dd, J =4.9, 8.3 Hz), 7.64-7.67 (1H, m), 8.42-8.47 (2H, br), DMSO: 385 (M +H)⁺FAB 078 1.58-1.78 (2H, m), 1.83 (2H, d, J = 12.2 Hz), 2.77 (1H, tt, J= 3.4, 12.2 Hz), 2.98 (1H, t, J = 12.2 Hz), 3.14 (1H, t, J = 12.2 Hz),4.15 (1H, d, J = 12.2 Hz), 4.31 (1H, d, J = 12.2 Hz), 5.10 (2H, s),6.84-6.90 (2H, m), 6.95 (1H, t, J = 2.0 Hz), 7.23 (1H, t, J = 7.8 Hz),7.31-7.48 (6H, m), 7.64-7.67 (1H, m), 8.42-8.47 (2H, m), DMSO: 389 (M +H)⁺FAB 079 461 (M + H)⁺FAB 080 1.40-1.66 (2H, m), 1.88-2.00 (2H, m),2.82-2.97 (1H, m), 2.97-3.14 (1H, m), 3.47-3.57 (1H, m), 4.01-4.17 (1H,m), 4.18-4.33 (1H, m), 5.26 (2H, s), 7.16-7.23 (1H, m), 7.30 (2H, d, J =9.0 Hz), 7.30-7.36 (2H, m), 7.41-7.46 (1H, m), 7.45-7.51 (1H, m), 7.62(1H, ddd, J = 8.3, 2.7, 1.5 Hz), 7.81 (2H, d, J = 8.8 Hz), 8.40 (1H, d,J = 2.4 Hz), 8.42 (1H, dd, J = 4.7, 1.5 Hz), DMSO: 471 (M + H)⁺FAB 0811.10-1.34 (2H, m) 1.70-1.80 (2H, m), 1.80-1.92 (1H, m), 2.80-2.95 (1H,m), 2.95-3.10 (1H, m), 2.70-3.95 (1H, br s), 3.34 (2H, d, J = 6.4 Hz),3.95-4.07 (1H, m), 4.11-4.23 (1H, m), 4.48 (2H, s), 7.25-7.38 (7H, m),7.44 (1H, dd, J = 8.3, 4.6 Hz), 7.62 (1H, ddd, J = 8.3, 2.6 1.2 Hz),DMSO: 327 (M + H)⁺FAB 082 462 (M⁺)FAB 083 418 (M + H)⁺FAB

TABLE 41 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 084 326 (M + H)⁺FAB085 2.49-2.62 (6H, m), 2.73-2.81 (2H, m), 3.40-3.66 (4H, m), 7.15-7.32(5H, m), 7.93 (1H, t, J = 1.9 Hz), 8.44 (1H, d, J = 2.4 Hz), 8.52 (1H,d, J = 2.0 Hz), DMSO: 346 (M + H)⁺FAB 086 2.49-2.62 (6H, m), 2.73-2.81(2H, m), 3.46 (2H, br), 3.62 (2H, br), 3.90 (3H, s), 7.15-7.32 (5H, m),8.11 (1H, dd, J = 2.0, 2.7 Hz), 8.70 (1H, d, J = 2.8 Hz), 8.94 (1H, d, J= 1.7 Hz), DMSO: 370 (M + H)⁺FAB 087 1.63-1.80 (2H, br), 1.97-2.11 (2H,br), 3.33-3.41 (1H, br), 3.43-3.58 (1H, br), 3.68-3.82 (1H, br),3.83-3.96 (1H, br), 4.72-4.80 (1H, m), 7.43-7.48 (2H, m), 7.59 (1H, dd,J = 3.2, 8.8 Hz), 7.62-7.67 (1H, m), 8.19 (1H, d, J = 2.2 Hz), 8.43-8.45(2H, m), DMSO: 334 (M + H)⁺FAB 088 1.39-1.65 (2H, m), 1.88-1.98 (2H, m),2.83-3.13 (2H, m), 3.46-3.55 (1H, m), 4.03-4.33 (2H, m), 5.23 (2H, s),7.29 (2H, d, J = 8.8 Hz), 7.33-7.51 (6H, m), 7.62 (1H, ddd, J = 1.5,2.9, 8.3 Hz), 7.80 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.42(1H, dd, J = 1.5, 4.9 Hz), DMSO: 453 (M + H)⁺FAB 089 1.40-1.65 (2H, m),1.88-1.99 (2H, m), 2.83-3.14 (2H, m), 3.47-3.57 (1H, m), 4.03-4.34 (2H,m), 5.30 (2H, s), 7.31 (2H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 4.9, 8.3Hz), 7.59-7.68 (2H, m), 7.79-7.87 (4H, m), 7.96-7.98 (1H, m), 8.40 (1H,d, J = 2.4 Hz), 8.42 (1H, dd, J = 1.5, 4.9 Hz), DMSO: 478 (M + H)⁺FAB090 469 (M + H)⁺FAB 091 473 (M + H)⁺FAB 092 334 (M + H)⁺FAB 093 424 (M +H)⁺FAB 094 419 (M + H)⁺FAB 095 487 (M + H)⁺FAB 096 385 (M + H)⁺FAB 097437 (M + H)⁺FAB 098 1.06-1.26 (2H, m), 1.37-1.44 (2H, m), 1.50-1.60 (1H,m), 1.73-1.82 (4H, m), 2.86 (1H, t, J = 12.2 Hz), 2.94 (6H, s), 3.05(1H, t, J = 12.2 Hz), 3.97-4.04 (3H, m), 4.18 (1H, d, J = 11.7 Hz), 6.96(2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.73 (1H, dd, J = 4.8,8.3 Hz), 7.96-8.01 (1H, m), 8.59 (1H, dd, J = 1.5, 4.8 Hz), 8.67 (1H, d,J = 2.4 Hz), DMSO: 412 (M + H)⁺FAB 099 1.02-1.22 (2H, m), 1.36-1.44 (2H,m), 1.49-1.61 (1H, m), 1.72-1.82 (4H, m), 2.75 (3H, d, J = 4.4 Hz), 2.87(1H, t, J = 12.2 Hz), 3.02 (1H, t, J = 12.2 Hz), 3.98-4.05 (3H, m), 4.17(1H, d, J = 12.2 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 4.4,8.3 Hz), 7.59-7.64 (1H, m), 7.78 (2H, d, J = 8.3 Hz), 8.22-8.27 (1H, m),8.38-8.43 (2H, m), DMSO: 398 (M + H)⁺FAB

TABLE 42 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 100 1.58-1.74 (2H,m), 1.90-2.06 (2H, m), 2.50 (3H, s), 3.30-3.95 (4H, m), 4.48-4.58 (3H,m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m),7.40-7.47 (1H, m), 7.54-7.57 (1H, m), 8.27-8.34 (1H, m), 8.34-8.42 (1H,m), DMSO: 495 (M + H)⁺FAB 101 1.40-1.64 (2H, m), 1.90-2.03 (2H, m),3.05-3.18 (1H, m), 3.20-3.34 (1H, m), 3.51-3.62 (1H, m), 3.88-4.01 (1H,m), 4.02-4.14 (1H, m), 5.16 (2H, s), 6.90-6.95 (1H, m), 6.98-7.03 (1H,m), 7.03-7.06 (1H, m), 7.13-7.19 (1H, m), 7.25-7.32 (3H, m), 7.41-7.47(1H, m), 7.72 (1H, dd, J = 8.8, 5.4 Hz), 7.99 (1H, ddd, J = 8.3, 2.4,1.0 Hz), 8.56-8.61 (1H, m), 8.67 (1H, d, J = 2.4 Hz), DMSO: 439 (M +H)⁺FAB 102 426 (M + H)⁺FAB 103 1.58-1.78 (2H, br), 1.97-2.11 (2H, br),3.30-3.60 (2H, br), 3.70-3.79 (1H, br), 3.85-3.96 (1H, br), 5.11-5.16(3H, m), 6.79 (1H, d, J = 8.8 Hz), 7.12-7.20 (1H, m), 7.25-7.30 (2H, m),7.40-7.50 (3H, m), 7.61-7.67 (1H, m), 7.93 (1H, d, J = 3.5 Hz),8.40-8.46 (2H, br), DMSO: 424 (M + H)⁺FAB 104 1.16-1.32 (2H, m)1.70-1.82 (2H, m), 1.79-1.91 (1H, m), 2.82-2.99 (1H, m), 2.95-3.12 (1H,m), 3.34 (2H, d, J = 6.3 Hz), 3.98-4.07 (1H, m), 4.11 (2H, dd, J = 5.8,1.4 Hz), 4.14-4.23 (1H, m), 6.36 (1H, ddd, J = 16.1, 5.8, 5.8 Hz), 6.61(1H, d, J = 16.1 Hz), 6.63 (1H, s), 7.21-7.29 (1H, m), 7.30-7.38 (2H,m), 7.40-7.49 (3H, m), 7.61 (1H, ddd, J = 8.3, 2.4, 1.4 Hz), 8.37-8.64(2H, m), 13.12 (1H, br s), DMSO: 353 (M + H)⁺FAB 105 471 (M + H)⁺FAB 106424 (M + H)⁺FAB 107 313 (M + H)⁺FAB 108 1.04-1.24 (2H, br), 1.36-1.43(2H, m), 1.48-1.61 (1H, m), 1.72-1.82 (4H, m), 2.87 (1H, t, J = 11.7Hz), 3.03 (1H, t, J = 11.7 Hz), 4.01 (1H, d, J = 11.7 Hz), 4.07 (2H, t,J = 6.4 Hz), 4.17 (1H, d, J = 11.7 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.44(1H, dd, J = 5.4, 8.3 Hz), 7.59-7.63 (1H, m), 7.76 (2H, d, J = 8.8 Hz),8.40-8.44 (2H, m), DMSO: 366 (M + H)⁺FAB 109 223 (M + H)⁺FAB 1101.23-1.43 (2H, m), 1.86 (2H, d, J = 12.7 Hz), 1.97-2.09 (1H, m), 2.93(1H, t, J = 12.2 Hz), 3.09 (1H, t, J = 12.2 Hz), 3.88 (2H, d, J = 12.7Hz), 4.07 (1H, d, J = 12.2 Hz), 4.23 (1H, d, J = 12.2 Hz), 6.90-6.96(3H, m), 7.26-7.31 (2H, m), 7.44 (1H, dd, J = 4.4, 8.3 Hz), 7.61-7.65(1H, m), 8.41-8.44 (2H, m), DMSO: 313 (M + H)⁺FAB 111 1.16-1.36 (2H, m),1.67-1.85 (5H, m), 2.93 (1H, t, J = 12.2 Hz), 3.08 (1H, t, J = 12.2 Hz),4.00 (1H, d, J = 12.2 Hz), 4.03 (2H, t, J = 6.3 Hz), 4.17 (1H, d, J =12.2 Hz), 6.90-6.96 (3H, m), 7.26-7.31 (2H, m), 7.78 (1H, dd, J = 4.9,8.3 Hz), 8.03-8.08 (1H, m), 8.62 (1H, dd, J = 1.0, 4.9 Hz), 8.72 (1H, d,J = 2.5 Hz), DMSO: 327 (M + H)⁺FAB

TABLE 43 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 112 1.05-1.25 (2H,m), 1.47-1.52 (2H, m), 1.58-1.68 (1H, m), 1.70-1.84 (4H, m), 2.62 (2H,t, J = 7.4 Hz), 2.87 (2H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz),4.00 (1H, d, J = 12.2 Hz), 4.15 (1H, d, J = 12.2 Hz), 7.15-7.22 (3H, m),7.25-7.30 (2H, m), 7.45 (1H, dd, J = 4.9, 8.3 Hz), 7.59-7.64 (1H, m),8.38-8.44 (2H, m), DMSO: 369 (M + H)⁺FAB 113 1.65-1.75 (2H, m), 1.83(2H, d, J = 12.2 Hz), 1.98-2.05 (2H, m), 2.72-2.80 (3H, m), 2.98 (1H, t,J = 12.2 Hz), 3.14 (1H, t, J = 12.2 Hz), 3.97 (2H, t, J = 6.3 Hz), 4.15(1H, d, J = 11.7 Hz), 4.31 (1H, d, J = 11.7 Hz), 6.75-6.79 (1H, m),6.83-6.87 (2H, m), 7.16-7.32 (6H, m), 7.46 (1H, dd, J = 4.9, 8.8 Hz),7.64-7.68 (1H, m), 8.42-8.47 (2H, br), DMSO: 417 (M + H)⁺FAB 1141.10-1.26 (2H, m), 1.35-1.45 (2H, m), 1.48-1.62 (1H, m), 1.70-1.82 (4H,m), 2.80-2.95 (1H, m), 2.96-3.11 (1H, m), 3.96 (2H, t, J = 6.4 Hz),3.97-4.07 (1H, m), 4.10-4.24 (1H, m), 6.89-6.95 (3H, m), 7.24-7.32 (2H,m), 7.44 (1H, dd, J = 8.3, 3.9 Hz), 7.61 (1H, ddd, J = 8.3, 2.9, 1.5Hz), 8.40 (1H, d, J = 2.9 Hz), 8.42 (1H, dd, J = 4.4, 1.5 Hz), DMSO: 341(M + H)⁺FAB 115 1.06-1.26 (2H, br), 1.37-1.45 (2H, m), 1.50-1.62 (1H,m), 1.72-1.88 (4H, m), 2.88 (1H, t, J = 13.2 Hz), 3.03 (1H, t, J = 13.2Hz), 4.01 (1H, d, J = 11.7 Hz), 4.13 (2H, t, J = 6.3 Hz), 4.18 (1H, d, J= 11.7 Hz), 7.02 (1H, t, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz),7.42-7.49 (2H, m), 7.53-7.64 (3H, m), 7.81 (1H, dd, J = 1.9, 7.8 Hz),8.40-8.44 (2H, m), DMSO: 384 (M + H)⁺FAB 116 1.05-1.25 (2H, br),1.36-1.45 (2H, m), 1.52-1.64 (1H, m), 1.73-1.83 (4H, m), 2.88 (1H, t, J= 12.7 Hz), 3.05 (1H, t, J = 12.7 Hz), 3.99-4.05 (3H, m), 4.18 (1H, d, J= 12.7 Hz), 7.05-7.09 (1H, m), 7.34 (2H, t, J = 8.3 Hz), 7.41-7.46 (2H,m), 7.73 (1H, dd, J = 4.9, 8.3 Hz), 7.92-8.02 (2H, m), 8.57-8.60 (1H,m), 8.67 (1H, d, J = 2.4 Hz), DMSO: 384 (M + H)⁺FAB 117 1.59-1.74 (2H,m), 1.96-2.03 (2H, m), 3.27-3.56 (2H, m), 3.70-3.95 (5H, m), 4.48-4.58(3H, m), 5.08 (2H, s), 6.85 (1H, d, J = 16.1 Hz), 6.96 (4H, s),7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.72 (1H, d, J= 16.1 Hz), 8.10 (1H, dd, J = 1.5 Hz, 2.4 Hz), 8.46 (1H, d, J = 2.4 Hz),8.75 (1H, d, J = 1.5 Hz), DMSO: 507 (M + H)⁺FAB 118 1.60-1.76 (2H, m),1.92-2.05 (2H, m), 3.30-3.55 (2H, m), 3.66-3.93 (2H, m), 4.48-4.56 (1H,m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m),7.39-7.47 (1H, m), 7.75-7.82 (1H, m), 8.35-8.40 (1H, m), 8.50 (1H, d, J= 2.5 Hz), DMSO: 441 (M + H)⁺FAB 119 452 (M + H)⁺FAB 120 449 (M + H)⁺FAB121 437 (M + H)⁺FAB 122 0.96-1.27 (5H, m), 1.60-1.86 (6H, m), 3.26-3.82(8H, m), 3.82 (2H, d, J = 6.3 Hz), 6.92-7.04 (3H, m), 7.36 (1H, t, J =8.3 Hz), 7.62-7.69 (1H, m), 7.90 (1H, br), 8.50-8.66 (2H, m), DMSO: 424(M + H)⁺FAB 123 437 (M + H)⁺FAB

TABLE 44 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 124 2.29 (3H, s),2.68 (2H, t, J = 7.3 Hz), 2.84 (2H, t, J = 7.3 Hz), 3.37-3.62 (8H, m),7.12 (2H, d, J = 7.9 Hz), 7.15-7.22 (1H, m), 7.24-7.32 (4H, m), 7.49(2H, d, J = 7.8 Hz), 7.80 (1H, dd, J = 4.9, 8.3 Hz), 8.05-8.10 (1H, m),8.63 (1H, dd, J = 1.0, 4.9 Hz), 8.73 (1H, d, J = 2.4 Hz), DMSO: 340 (M +H)⁺FAB 125 312 (M + H)⁺FAB 126 3.46-3.59 (2H, m), 3.61-3.77 (4H, m),3.78-3.92 (2H, m), 7.30 (1H, d, J = 15.5 Hz), 7.36-7.45 (2H, m), 7.48(1H, d, J = 8.0 Hz), 7.54 (1H, d, J = 15.5 Hz), 7.71-7.76 (1H, m), 7.80(1H, dd, J = 8.6, 4.8 Hz), 8.07-8.12 (1H, m), 8.64 (1H, dd, J = 5.3, 1.1Hz), 8.75 (1H, d, J = 2.2 Hz), DMSO: 338 (M + H)ES 127 342 (M + H)⁺ESI128 326 (M + H)⁺FAB 129 341 (M + H)⁺ESI 130 354 (M + H)⁺FAB 131 352 (M +H)⁺FAB 132 369 (M + H)⁺FAB 133 355 (M + H)⁺FAB 134 426 (M + H)⁺FAB 135457 (M + H)⁺FAB 136 457 (M + H)⁺FAB 137 453 (M + H)⁺FAB 138 3.30-3.82(8H, br), 5.08 (2H, s), 7.02 (1H, d, J = 7.8), 7.06-7.08 (1H, m),7.11-7.14 (1H, m), 7.38-7.47 (4H, m), 7.53 (1H, s), 7.70-7.80 (1H, br),7.95-8.08 (1H, br), 8.58 (2H, m), DMSO: 452 (M + H)⁺FAB 139 385 (M +H)⁺ESI 140 385 (M + H)⁺ESI 141 385 (M + H)⁺ESI 142 348 (M + H)⁺FAB 143362 (M + H)⁺FAB 144 2.29 (3H, s), 3.40-3.71 (8H, m), 5.12 (2H, s), 7.12(2H, d, J = 7.8 Hz), 7.30-7.41 (5H, m), 7.49 (2H, d, J = 8.3 Hz), 7.80(1H, dd, J = 5.4, 8.3 Hz), 8.02-8.11 (1H, m), 8.63 (1H, d, J = 5.4 Hz),8.73 (1H, d, J = 1.9 Hz), DMSO: 342 (M + H)⁺FAB 145 329 (M + H)⁺FAB 146341 (M + H)⁺FAB 147 3.44-3.71 (8H, m), 5.18 (2H, s), 7.10 (2H, d, J =8.8 Hz), 7.38-7.50 (6H, m), 7.54 (1H, s), 7.61-7.67 (1H, m), 8.40-8.44(2H, m), DMSO: 452 (M + H)⁺FAB 148 432 (M + H)⁺FAB 149 3.40-3.71 (8H,m), 5.28 (2H, s), 7.12 (2H, d, J = 8.8 Hz), 7.40-7.48 (3H, m), 7.62-7.68(2H, m), 7.72 (1H, d, J = 7.8 Hz), 7.79 (1H, d, J = 7.3 Hz), 7.84 (1H,s), 8.42-8.46 (2H, m), DMSO: 486 (M + H)⁺FAB

TABLE 45 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 150 448 (M + H)⁺FAB151 3.43-3.74 (8H, m), 5.23 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.40-7.48(3H, m), 7.60-7.67 (2H, m), 7.79-7.85 (2H, m), 7.95 (1H, br), 8.42-8.46(2H, m), DMSO: 443 (M + H)⁺FAB 152 3.43-3.74 (8H, m), 5.20 (2H, s), 7.09(2H, d, J = 8.8 Hz), 7.14-7.26 (3H, m), 7.40-7.49 (3H, m), 7.60-7.68(1H, m), 8.42-8.46 (2H, m), DMSO: 454 (M + H)⁺FAB 153 502 (M + H)⁺FAB154 3.42-3.74 (8H, m), 5.33 (2H, s), 7.13 (2H, d, J = 8.8 Hz), 7.42-7.49(3H, m), 7.63-7.67 (1H, m), 7.72 (1H, t, J = 7.8 Hz), 7.94 (1H, d, J =8.1 Hz), 8.19-8.23 (1H, m), 8.34 (1H, br), 8.42-8.46 (2H, m), DMSO: 463(M + H)⁺ESI 155 3.43-3.74 (8H, m), 5.14 (2H, s), 7.07 (2H, d, J = 8.8Hz), 7.23 (2H, t, J = 8.8 Hz), 7.40-7.56 (5H, m), 7.60-7.67 (1H, m),8.40-8.46 (2H, m), DMSO: 436 (M + H)⁺FAB 156 436 (M + H)⁺FAB 157 419(M + H)⁺FAB 158 439 (M + H)⁺ESI 159 3.43-3.74 (8H, m), 5.17 (2H, s),7.10 (2H, d, J = 8.8 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.40-7.50 (4H, m),7.55 (1H, d, J = 7.8 Hz), 7.63-7.70 (2H, m), 8.42-8.47 (2H, m), DMSO:496, (M + H)⁺FAB 160 3.07 (2H, t, J = 7.0 Hz), 3.43-3.74 (8H, m), 4.26(2H, t, J = 6.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.24-7.48 (7H, m),7.62-7.67 (1H, m), 8.42-8.46 (2H, m), DMSO: 466 (M + H)⁺FAB 161 443 (M +H)⁺FAB 162 544 (M + H)⁺FAB 163 461 (M + H)⁺FAB 164 477 (M + H)⁺FAB 165477 (M + H)⁺FAB 166 473 (M + H)⁺FAB 167 476 (M + H)⁺FAB 168 346 (M +H)⁺FAB 169 307 (M + H)⁺FAB 170 1.00-1.20 (2H, m), 1.18-1.25 (2H, m),1.35-1.50 (1H, m), 1.45-1.58 (2H, m), 1.68-1.78 (2H, m), 2.14 (2H, t, J= 7.4 Hz), 2.77-2.91 (1H, m), 2.92-3.09 (1H, m), 3.90-4.07 (1H, m),4.10-4.22 (1H, m), 6.68 (1H, br s), 7.22 (1H, br s), 7.45 (1H, dd, J =8.3, 4.9 Hz), 7.56-7.66 (1H, m), 8.25-8.50 (2H, m), DMSO: 292 (M +H)⁺FAB 171 354 (M + H)⁺FAB 172 341 (M + H)⁺FAB

TABLE 46 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 173 1.54-1.79 (2H,m), 1.82-1.96 (2H, m), 2.62 (1H, dddd, J = 11.2, 11.2, 3.4, 3.4 Hz),2.88-3.07 (1H, m), 3.04-3.23 (1H, m), 4.00-4.16 (1H, m), 4.16-4.32 (1H,m), 6.99-7.07 (1H, m), 7.25-7.34 (2H, m), 7.45 (1H, dd, J = 8.3, 4.9Hz), 7.58-7.65 (2H, m), 7.65 (1H, ddd, J = 8.3, 2.4, 1.4 Hz), 8.41-8.46(2H, m), 9.94 (1H, s), DMSO: 326 (M + H)⁺FAB 174 1.42-1.65 (2H, m),1.65-1.79 (2H, m), 2.35 (1H, dddd, J = 11.3, 11.3, 3.4, 3.4 Hz), 2.72(2H, t, J = 7.3 Hz), 2.83-2.99 (1H, m), 3.00-3.16 (1H, m), 3.28 (2H, t,J = 7.3 Hz), 3.91-4.06 (1H, m), 4.08-4.23 (1H, m), 7.16-7.23 (3H, m),7.25-7.33 (2H, m), 7.44 (1H, dd, J = 8.3, 4.9 Hz), 7.62 (1H, ddd, J =8.3, 2.5, 1.0 Hz), 7.90 (1H, br t, J = 5.4 Hz), 8.41 (1H, d, J = 2.5Hz), 8.43 (1H, dd, J = 4.9, 1.5 Hz), DMSO: 354 (M + H)⁺FAB 175 1.40 (2H,tt, J = 7.3, 7.3 Hz), 1.56 (2H, tt, J = 7.3, 7.3 Hz), 1.47-1.66 (2H, m),1.68-1.79 (2H, m), 2.30-2.40 (1H, m), 2.57 (2H, t, J = 7.8 Hz),2.86-2.94 (1H, m), 3.00-3.08 (1H, m), 3.07 (2H, dt, J = 6.9, 6.9 Hz),3.93-4.07 (1H, m), 4.10-4.24 (1H, m), 7.12-7.21 (3H, m), 7.23-7.31 (2H,m), 7.44 (1H, dd, J = 8.3, 4.9 Hz), 7.62 (1H, ddd, J = 8.3, 3.0, 1.5Hz), 7.81 (1H, br t, J = 5.4 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.43 (1H,dd, J = 4.4, 3.0 Hz), DMSO: 382 (M + H)⁺FAB 176 0.85 (3H, t, J = 6.4Hz), 1.17-1.32 (10H, m), 1.45-1.58 (2H, m), 1.54-1.76 (2H, m), 1.80-1.93(2H, m), 2.51 (2H, t, J = 6.4 Hz), 2.55-2.64 (1H, m), 2.88-3.04 (1H, m),2.99-3.20 (1H, m), 4.00-4.14 (1H, m), 4.15-4.30 (1H, m), 7.10 (2H, d, J= 8.3 Hz), 7.45 (1H, dd, J = 8.3, 4.4 Hz), 7.50 (2H, d, J = 8.3 Hz),7.64 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 8.40-8.46 (2H, m), 9.85 (1H, s),DMSO: 438 (M + H)⁺FAB 177 411 (M + H)⁺FAB 178 411 (M + H)⁺FAB 1791.58-1.78 (2H, m), 1.85 (2H, d, J = 12.2 Hz), 2.75-2.83 (1H, m), 3.03(1H, t, J = 12.2 Hz), 3.18 (1H, t, J = 12.2 Hz), 4.15 (1H, d, J = 12.7Hz), 4.32 (1H, d, J = 12.7 Hz), 4.42 (2H, s), 6.80 (1H, dd, J = 2.0, 8.3Hz), 6.88-6.92 (2H, m), 7.24 (1H, t, J = 8.3 Hz), 7.38 (1H, br), 7.52(1H, br), 7.77 (1H, dd, J = 5.3, 8.3 Hz), 8.02-8.09 (1H, m), 8.62 (1H,d, J = 5.3 Hz), 8.74 (1H, d, J = 2.0 Hz), DMSO: 356 (M + H)⁺FAB 180 467(M + H)⁺ESI 181 411 (M + H)⁺FAB 182 382 (M + H)⁺FAB 183 398 (M + H)⁺FAB184 454 (M + H)⁺FAB 185 502 (M + H)⁺FAB 186 480 (M + H)⁺FAB 187 410 (M +H)⁺FAB 188 488 (M + H)⁺FAB 189 370 (M + H)⁺FAB 190 432 (M + H)⁺FAB

TABLE 47 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 191 397 (M + H)⁺FAB192 409 (M + H)⁺ESI 193 386 (M + H)⁺FAB 194 371 (M + H)⁺FAB 195 357 (M +H)⁺ESI 196 337 (M + H)⁺FAB 197 1.20-1.32 (2H, m), 1.28-1.48 (2H, m),1.47-1.62 (4H, m), 1.70-1.86 (2H, m), 2.06 (2H, t, J = 7.3 Hz), 2.56(2H, t, J = 7.3 Hz), 2.98-3.10 (1H, m), 3.12-3.25 (1H, m), 3.73-3.86(1H, m), 3.83-3.97 (1H, m), 3.98-4.13 (1H, m), 7.12-7.21 (3H, m),7.22-7.30 (2H, m), 7.45 (1H, dd, J = 8.3, 4.4 Hz), 7.62 (1H, ddd, J =8.3, 2.5, 1.5 Hz), 7.78 (1H, br d, J = 7.3 Hz), 8.41 (1H, d J = 2.5 Hz),8.43 (1H, dd, J = 4.9, 1.5 Hz), DMSO: 396 (M + H)⁺FAB 198 315 (M +H)⁺FAB 199 1.57-1.75 (2H, br), 1.90-2.03 (2H, br), 3.28-3.40 (1H, br),3.43-3.57 (1H, br), 3.64-3.79 (1H, br), 3.82-3.93 (1H, br), 4.38-4.46(1H, m), 6.69 (2H, brd, J = 8.8 Hz), 6.83 (2H, brd, J = 8.8 Hz), 7.44(1H, dd, J = 4.9, 8.3 Hz), 7.61-7.66 (1H, m), 8.43 (2H, d, J = 3.0 Hz),8.96 (1H, s), DMSO: 315 (M + H)⁺FAB 200 0.96-1.30 (5H, m), 1.60-1.83(8H, m), 1.94-2.09 (2H, m), 3.33-3.44 (1H, br), 3.48-3.60 (1H, br),3.70-3.80 (1H, br), 3.75 (2H, d, J = 6.3 Hz), 3.85-3.95 (1H, br),4.64-4.70 (1H, m), 6.50-6.60 (3H, m), 7.17 (1H, t, J = 13.7 Hz), 7.87(1H, dd, J = 5.4, 8.3 Hz), 8.18 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J =5.4 Hz), 8.82 (1H, d, J = 1.9 Hz), DMSO: 411 (M + H)⁺FAB 201 425 (M +H)⁺FAB 202 1.60-1.76 (2H, br), 1.95-2.07 (2H, br), 3.33-3.45 (1H, br),3.47-3.58 (1H, br), 3.70-3.80 (1H, br), 3.85-3.96 (1H, br), 4.63-4.70(1H, m), 5.13 (2H, s), 6.59-6.64 (3H, m), 7.13-7.23 (2H, m), 7.26-7.31(2H, m), 7.41-7.48 (1H, m), 7.78 (1H, dd, J = 5.4, 8.8 Hz), 8.06 (1H,brd, J = 7.3 Hz), 8.62 (1H, d, J = 4.8 Hz), 8.73 (1H, d, J = 2.4 Hz),DMSO: 423 (M + H)⁺FAB 203 1.60-1.80 (2H, br), 1.90-2.07 (2H, br),3.33-3.45 (1H, br), 3.47-3.60 (1H, br), 3.70-3.81 (1H, br), 3.85-3.96(1H, br), 4.63-4.71 (1H, m), 5.12 (2H, s), 6.60-6.69 (3H, m), 7.18-7.28(3H, m), 7.39-7.47 (1H, m), 7.56 (1H, dt, J = 1.4, 7.8 Hz), 7.83-7.89(1H, m), 8.15-8.20 (1H, m), 8.68 (1H, brd, J = 5.4 Hz), 8.81 (1H, br),DMSO: 423 (M + H)⁺FAB 204 423 (M + H)⁺FAB 205 1.60-1.84 (2H, br),1.94-2.06 (2H, br), 3.30-3.42 (1H, br), 3.45-3.56 (1H, br), 3.70-3.80(1H, br), 3.84-3.96 (1H, br), 4.61-4.69 (1H, m), 5.16 (2H, m), 6.61 (1H,d, J = 2.5 Hz), 6.63 (1H, d, J = 2.5 Hz), 6.66 (1H, t, J = 1.9 Hz), 7.20(1H, t, J = 7.8 Hz), 7.46 (1H, dd, J = 4.9, 8.3 Hz), 7.60-7.67 (2H, m),7.78-7.83 (2H, m), 7.92 (1H, br), 8.45 (2H, m), DMSO: 430 (M + H)⁺FAB

TABLE 48 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 206 1.59-1.76 (2H,br), 1.91-2.07 (2H, br), 3.33-3.42 (1H, br), 3.45-3.56 (1H, br),3.69-3.80 (1H, br), 3.82-3.94 (1H, br), 4.45-4.55 (1H, m), 5.06 (2H, s),6.96 (4H, s), 7.36-7.46 (3H, m), 7.50 (1H, br), 7.75 (1H, dd, J = 4.9,8.3 Hz), 8.02 (1H, d, J = 8.3 Hz), 8.60 (1H, d, J = 4.9 Hz), 8.70 (1H,d, J = 2.5 Hz), DMSO: 439 (M + H)⁺FAB 207 0.88-1.01 (2H, m), 1.09-1.30(3H, m), 1.40-1.51 (1H, m), 1.55-1.76 (9H, m), 1.93-2.05 (2H, m),3.30-3.42 (1H, br), 3.46-3.60 (1H, br), 3.70-3.80 (1H, br), 3.85-3.95(3H, m), 4.45-4.55 (1H, m), 6.84-6.94 (4H, m), 7.66 (1H, dd, J = 4.9,8.3 Hz), 7.98 (1H, d, J = 8.3 Hz), 8.58 (1H, d, J = 4.8 Hz), 8.66 (1H,d, J = 1.9 Hz), DMSO: 425 (M + H)⁺FAB 208 1.60-1.80 (2H, br), 1.94-2.07(2H, br), 3.31-3.44 (1H, br), 3.46-3.60 (1H, br), 3.69-3.82 (1H, br),3.84-3.96 (1H, br), 4.50-4.58 (1H, m), 5.08 (2H, s), 6.97 (4H, s),7.20-7.28 (2H, m), 7.39-7.45 (1H, m), 7.54 (1H, dt, J = 1.5, 7.3 Hz),7.81 (1H, dd, J = 5.4, 8.3 Hz), 8.10 (1H, brd, J = 8.3 Hz), 8.64 (1H, d,J = 5.3 Hz), 8.77 (1H, s), DMSO: 423 (M + H)⁺FAB 209 1.60-1.80 (2H, br),1.94-2.07 (2H, br), 3.31-3.44 (1H, br), 3.46-3.60 (1H, br), 3.69-3.80(1H, br), 3.82-3.96 (1H, br), 4.48-4.58 (1H, m), 5.03 (2H, s), 6.96 (4H,s), 7.18-7.26 (2H, m), 7.45-7.51 (2H, m), 7.78-7.89 (1H, m), 8.07-8.19(1H, m), 8.67 (1H, brd, J = 4.9 Hz), 8.80 (1H, br), DMSO: 423 (M +H)⁺FAB 210 1.60-1.75 (2H, br), 1.91-2.06 (2H, br), 3.30-3.42 (1H, br),3.45-3.56 (1H, br), 3.70-3.80 (1H, br), 3.84-3.96 (1H, br), 4.49-4.56(1H, m), 5.11 (2H, m), 6.96 (4H, s), 7.46 (1H, dd, J = 4.8, 8.6 Hz),7.61 (1H, t, J = 7.5 Hz), 7.64-7.68 (1H, m), 7.76-7.83 (2H, m), 7.90(1H, br), 8.43-8.47 (2H, m), DMSO: 430 (M + H)⁺FAB 211 463 (M + H)⁺FAB212 1.58-1.74 (2H, br), 1.91-2.05 (2H, br), 3.30-3.42 (1H, br),3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.83-3.94 (1H, br), 4.48-4.55(1H, m), 5.09 (2H, s), 6.96 (4H, s), 7.36-7.50 (3H, m), 7.59 (1H, d, J =7.9 Hz), 7.62-7.66 (1H, m), 7.84 (1H, d, J = 7.8 Hz), 7.96 (1H, s), 8.00(1H, br), 8.41-8.45 (2H, m), DMSO: 448 (M + H)⁺FAB 213 497 (M + H)⁺FAB214 484 (M + H)⁺FAB 215 488 (M + H)⁺FAB 216 0.96-1.08 (2H, m), 1.10-1.31(3H, m), 1.60-1.83 (8H, m), 1.91-2.05 (2H, m), 3.25-3.57 (2H, m),3.65-3.95 (7H, m), 4.46-4.54 (1H, m), 6.81-6.87 (2H, m), 6.89-6.95 (2H,m), 8.13 (1H, dd, J = 2.0 Hz, 2.4 Hz), 8.70 (1H, d, J = 2.4 Hz), 8.94(1H, d, J = 2.0 Hz), DMSO: 469 (M + H)⁺FAB 217 1.58-1.76 (2H, m),1.90-2.04 (2H, m), 2.80-4.00 (4H, m), 4.38-4.47 (1H, m), 6.70 (2H, d, J= 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 8.05-8.10 (1H, m), 8.66 (1H, d, J =2.4 Hz), 8.90-8.94 (1H, m), DMSO: 359 (M + H)⁺FAB

TABLE 49 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 218 1.60-1.78 (2H,m), 1.93-2.05 (2H, m), 3.35-3.95 (4H, m), 4.48-4.56 (1H, m), 5.07 (2H,s), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H,m), 8.07-8.10 (1H, m), 8.67 (1H, d, J = 2.4 Hz), 8.91-8.94 (1H, m),13.30-13.75 (1H, br), DMSO: 467 (M + H)⁺FAB 219 341 (M + H)⁺FAB 220 327(M + H)⁺ESI 221 449 (M + H)⁺FAB 222 325 (M + H)⁺ESI 223 353 (M − H)⁻FAB224 355 (M − H)⁻FAB 225 1.12-1.32 (2H, m), 1.45-1.60 (3H, m), 1.79 (2H,d, J = 11.7 Hz), 2.63 (2H, t, J = 7.5 Hz), 2.87 (1H, t, J = 12.2 Hz),3.02 (1H, t, J = 12.2 Hz), 4.01 (1H, d, J = 12.7 Hz), 4.18 (1H, t, J =12.7 Hz), 7.15-7.31 (5H, m), 8.05 (1H, dd, J = 2.0, 2.4 Hz), 8.65 (1H,d, J = 2.4 Hz), 8.92 (1H, t, J = 2.0 Hz), 13.59 (1H, br s), DMSO: 355(M + H)⁺FAB 226 470 (M + H)⁺FAB 227 410 (M + H)⁺FAB 228 0.88-1.00 (2H,m), 1.08-1.28 (4H, m), 1.39-1.51 (1H, m), 1.54-1.77 (10H, m), 1.91-2.05(2H, m), 3.20-3.96 (6H, m), 4.46-4.54 (1H, m), 6.83-6.88 (2H, m),6.90-6.95 (2H, m), 8.08 (1H, dd, J = 2.0 Hz, 2.4 Hz), 8.66 (1H, d, J =2.4 Hz), 8.92 (1H, d, J = 1.5 Hz), DMSO: 469 (M + H)⁺FAB 229 483 (M +H)⁺FAB 230 474 (M + H)⁺FAB 231 356 (M + H)⁺FAB 232 371 (M + H)⁺FAB 2331.58-1.78 (2H, m), 1.91-2.06 (2H, m), 3.25-3.95 (7H, m), 4.49-4.56 (1H,m), 5.02 (2H, s), 6.86-7.03 (7H, m), 7.30 (1H, dd, J = 7.8 Hz, 8.3 Hz),8.07 (1H, s), 8.64 (1H, s), 8.92 (1H, s), DMSO: 479 (M + H)⁺FAB 2341.60-1.80 (2H, br), 1.92-2.10 (2H, br), 3.30-3.60 (2H, br), 3.70-3.80(1H, br), 3.85-3.96 (1H, br), 4.60-4.70 (1H, m), 5.12 (2H, s), 6.58-6.68(3H, m), 7.24-7.32 (4H, m), 7.42-7.50 (1H, m), 8.09 (1H, t, J = 2.4 Hz),8.67 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.9 Hz), 13.50 (1H, br),DMSO: 467 (M + H)⁺FAB 235 1.60-1.80 (2H, br), 1.92-2.10 (2H, br),3.30-3.60 (2H, br), 3.70-3.80 (1H, br), 3.85-3.96 (1H, br), 4.60-4.72(1H, m), 5.16 (2H, s), 6.60-6.68 (3H, m), 7.21 (1H, t, J = 8.3 Hz), 7.62(1H, t, J = 8.3 Hz), 7.78-7.84 (2H, m), 7.92 (1H, s), 8.09 (1H, dd, J =1.4, 2.4 Hz), 8.67 (1H, d, J = 3.0 Hz), 8.93 (1H, d, J = 1.4 Hz), 13.50(1H, br), DMSO: 474 (M + H)⁺FAB

TABLE 50 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 236 1.60-1.74 (2H,m), 1.91-2.06 (2H, m), 3.30-3.95 (7H, m), 4.47-4.57 (1H, m), 5.14 (2H,s), 6.96 (4H, s), 7.55 (1H, dd, J = 7.4 Hz, 7.8 Hz), 7.72 (1H, d, J =7.4 Hz), 7.92 (1H, d, J = 7.8 Hz), 8.04 (1H, s), 8.08 (1H, dd, J = 2.0Hz, 2.4 Hz), 8.67 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), DMSO:507 (M + H)⁺FAB 237 455 (M + H)⁺FAB 238 369 (M + H)⁺ESI 239 385 (M +H)⁺ESI 240 371 (M + H)⁺ESI 241 398 (M + H)⁺FAB 242 0.73-2.10 (17H, m),3.20-4.02 (6H, br), 4.60-4.70 (1H, m), 6.49-6.60 (3H, m), 7.17 (1H, t, J= 8.3 Hz), 8.09 (1H, br), 8.67 (1H, d, J = 2.0 Hz), 8.92 (1H, br),13.40-13.80 (1H, br), DMSO: 469 (M + H)⁺FAB 243 370 (M + H)⁺FAB 244 524(M + H)⁺FAB 245 1.60-1.77 (2H, m), 1.92-2.06 (2H, m), 3.35-3.96 (4H, m),4.48-4.56 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m),7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.63-7.71 (1H, m), 8.07-8.10 (1H,m), 8.14-8.23 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.90 (1H, d, J = 1.9Hz), DMSO: 466 (M + H)⁺FAB 246 1.59-1.78 (2H, m), 1.91-2.05 (2H, m),3.25-3.57 (2H, m), 3.68-3.96 (2H, m), 4.47-4.56 (1H, m), 5.04 (2H, s),6.95 (4H, s), 7.29-7.46 (5H, m), 7.64-7.70 (1H, m), 8.04 (1H, dd, J =1.9 Hz, 2.4 Hz), 8.15-8.21 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.89 (1H,d, J = 1.9 Hz), DMSO: 448 (M + H)⁺FAB 247 397 (M + H)⁺FAB 248 451 (M +H)⁺FAB 249 523 (M + H)⁺FAB 250 579 (M + H)⁺ESI 251 524 (M + H)⁺FAB 252577 (M + H)⁺FAB 253 537 (M + H)⁺FAB 254 577 (M + H)⁺FAB 255 1.58-1.78(2H, br), 1.93-2.06 (2H, br), 3.32-3.42 (3H, m), 3.48-3.58 (3H, m),3.70-3.80 (1H, br), 3.85-3.95 (1H, br), 4.48-4.58 (1H, m), 4.92 (1H,br), 5.07 (2H, s), 6.95 (4H, s), 7.15 (1H, dt, J = 2.4, 8.8 Hz),7.24-7.30 (2H, m), 7.41-7.47 (1H, m), 8.14 (1H, t, J = 2.0 Hz), 8.63(1H, d, J = 2.4 Hz), 8.75 (1H, t J = 5.3 Hz), 8.93 (1H, d, J = 1.4 Hz),DMSO: 510 (M + H)⁺FAB

TABLE 51 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 256 586 (M + H)⁺FAB257 549 (M + H)⁺FAB 258 1.13-1.33 (2H, br), 1.66 (2H, d, J = 12.7 Hz),1.73-1.85 (1H, m), 2.57 (2H, d, J = 6.8 Hz), 2.86 (1H, t, J = 12.2 Hz),3.02 (1H, t, J = 12.2 Hz), 4.03 (1H, d, J = 12.2 Hz), 4.20 (1H, d, J =12.2 Hz), 7.18-7.23 (3H, m), 7.27-7.32 (2H, m), 7.48 (1H, s), 7.60 (1H,t, J = 7.8 Hz), 7.93 (2H, d, J = 7.3 Hz), 8.01 (1H, t, J = 2.4 Hz), 8.13(1H, s), 8.23 (1H, s), 8.44 (1H, d, J = 2.4 Hz), 8.84 (1H, d, J = 2.0Hz), DMSO: 416 (M + H)⁺FAB 259 374 (M + H)⁺FAB 260 1.60-1.75 (2H, m),1.92-2.04 (2H, m), 3.30-3.91 (4H, m), 4.49-4.56 (1H, m), 5.07 (2H, s),6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.39-7.47 (2H, m),7.92 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz), DMSO: 438 (M +H)⁺FAB 261 550 (M + H)⁺FAB 262 1.58-1.75 (2H, m), 1.90-2.05 (2H, m),3.30-3.57 (2H, m), 3.67-3.95 (2H, m), 4.13 (2H, s), 4.48-4.55 (1H, m),5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m),7.40-7.47 (1H, m), 7.61-7.64 (1H, m), 8.35-8.39 (1H, m), 8.40-8.44 (1H,m), DMSO: 510 (M⁺)FAB 263 1.58-1.74 (2H, m), 1.91-2.04 (2H, m), 2.50(3H, s), 3.30-3.95 (4H, m), 4.48-4.58 (3H, m), 5.07 (2H, s), 5.40 (1H,t, J = 5.9 Hz), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m),7.40-7.47 (1H, m), 7.53-7.56 (1H, m), 8.28-8.31 (1H, m), 8.36-8.39 (1H,m), DMSO: 453 (M + H)⁺FAB 264 1.59-1.74 (2H, m), 1.96-2.03 (2H, m),3.27-3.57 (2H, m), 3.70-3.65 (2H, m), 4.48-4.58 (3H, m), 5.08 (2H, s),6.72 (1H, d, J = 16.1 Hz), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30(2H, m), 7.40-7.47 (1H, m), 7.64 (1H, d, J = 16.1 Hz), 8.07 (1H, dd, J =2.0 Hz, 2.0 Hz), 8.45 (1H, d, J = 2.5 Hz), 8.71 (1H, d, J = 1.4 Hz),12.40-12.74 (1H, br), DMSO: 493 (M + H)⁺FAB 265 445 (M + H)⁺FAB 2661.10-1.33 (2H, m), 1.45-1.61 (3H, m), 1.75-1.87 (2H, br), 2.64 (2H, t, J= 7.6 Hz), 2.81-3.10 (2H, br), 3.92-4.27 (2H, br), 7.14-7.32 (5H, m),7.43-7.52 (1H, m), 7.60 (1H, d, J = 8.0 Hz), 7.90-7.98 (2H, m),8.05-8.17 (2H, m), 8.21-8.27 (1H, m), 8.48 (1H, d, J = 2.4 Hz), 8.87(1H, d, J = 2.4 Hz), DMSO 267 380 (M + H)⁺FAB 268 1.33-1.56 (2H, m),1.77-1.88 (2H, m), 2.37-2.48 (1H, m), 2.93-3.04 (1H, m), 3.09-3.21 (1H,m), 3.98-4.12 (1H, m), 4.14-4.28 (1H, m), 6.31 (1H, dd, J = 16.1, 6.8Hz), 6.45 (1H, d, J = 16.1 Hz), 7.18-7.24 (1H, m), 7.28-7.35 (2H, m),7.38-7.48 (3H, m), 7.63 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 8.41-8.45 (2H,m), DMSO-d6: 309 (M + H)⁺FAB 269 1.33-1.56 (2H, m), 1.67-1.79 (2H, m),2.73-2.88 (1H, m), 2.88-3.02 (1H, m), 2.88-3.02 (1H, m), 3.04-3.18 (1H,m), 3.95-4.07 (1H, m), 4.10-4.23 (1H, m), 5.54 (1H, dd, J = 11.8, 9.7Hz), 6.42 (1H, d, J = 11.8 Hz), 7.23-7.34 (3H, m), 7.35-7.42 (2H, m),7.44 (1H, dd, J = 8.3, 4.8 Hz), 7.63 (1H, ddd, J = 8.3, 2.4, 1.5 Hz),8.40-8.45 (2H, m), DMSO: 309 (M + H)⁺FAB 270 1.08-1.30 (2H, m),1.43-1.60 (3H, m), 1.73-1.82 (2H, br), 2.63 (2H, t, J = 7.8 Hz),2.77-3.08 (2H, br), 3.92-4.20 (2H, br), 7.13-7.32 (5H, m), 8.04 (1H, dd,J = 2.0, 2.4 Hz), 8.45 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 2.0 Hz),DMSO: 389 (M⁺)FAB

TABLE 52 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 271 0.78-0.94 (2H,m), 1.00-1.24 (10H, m), 1.37-1.50 (1H, m), 1.57-1.76 (7H, m), 2.80-2.92(1H, br), 2.96-3.08 (1H, br), 3.93-4.05 (1H, br), 4.08-4.21 (1H, br),7.68 (1H, dd, J = 4.8, 7.6 Hz), 7.93-8.00 (1H, m), 8.58 (1H, d, J = 7.6Hz), 8.62-8.69 (1H, m), DMSO: 317 (M + H)⁺FAB 272 0.79-0.92 (2H, m),1.04-1.29 (10H, m), 1.36-1.49 (1H, m), 1.57-1.76 (7H, m), 2.80-2.92 (1H,br), 2.95-3.08 (1H, br), 3.90 (3H, s), 3.92-4.05 (1H, br), 4.08-4.21(1H, br), 8.09 (1H, dd, J = 2.0, 2.4 Hz), 8.68 (1H, d, J = 2.4 Hz), 8.93(1H, d, J = 2.0 Hz), DMSO: 375 (M + H)⁺FAB 273 1.44-1.59 (2H, m),1.77-1.88 (2H, m), 2.37-2.48 (1H, m), 2.93-3.07 (1H, m), 3.07-3.23 (1H,m), 3.98-4.14 (1H, m), 4.14-4.29 (1H, m), 6.31 (1H, dd, J = 16.1, 6.9Hz), 6.45 (1H, d, J = 16.1 Hz), 7.17-7.25 (1H, m), 7.27-7.36 (2H, m),7.38-7.44 (2H, m), 8.05-8.09 (1H, m), 8.67 (1H, d, J = 2.4 Hz), 8.92(1H, d, J = 1.5 Hz), 13.60 (1H, br s), DMSO: 353 (M + H)⁺FAB 2741.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J= 8.3 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.16-7.34 (4H, m), 8.04(1H, dd, J = 1.5, 2.0 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J =1.9 Hz), 13.60 (1H, s), DMSO: 389 (M + H)⁺FAB 275 380 (M + H)⁺FAB 2761.10-1.30 (2H, m), 1.44-1.60 (3H, m), 1.73-1.82 (2H, m), 2.60 (2H, t, J= 7.3 Hz), 2.80-3.10 (2H, m), 3.74 (3H, s), 3.95-4.24 (2H, m), 6.72-6.81(3H, m), 7.19 (1H, t, J = 8.3 Hz), 8.04 (1H, t, J = 1.9 Hz), 8.64 (1H,d, J = 2.4 Hz), 8.92 (1H, d, J = 1.5 Hz), 13.60 (1H, s)DMSO: 385 (M +H)⁺FAB 277 1.10-1.30 (2H, m), 1.44-1.60 (3H, m), 1.73-1.82 (2H, m), 2.60(2H, t, J = 7.4 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 6.95-7.10(3H, m), 7.29-7.36 (1H, m), 8.04 (1H, t, J = 2.0 Hz), 8.65 (1H, d, J =2.4 Hz), 8.92 (1H, d, J = 1.9 Hz), 13.60 (1H, s), DMSO: 373 (M + H)⁺FAB278 380 (M + H)⁺FAB 279 396 (M − H)⁻FAB 280 426 (M + H)⁺FAB 2811.10-1.33 (2H, m), 1.46-1.59 (1H, m), 1.54-1.66 (2H, m), 1.75-1.87 (2H,m), 2.68 (2H, dd, J = 7.6, 7.6 Hz), 2.79-2.94 (1H, m), 2.95-3.10 (1H,m), 3.95-4.09 (1H, m), 4.11-4.25 (1H, m), 7.29-7.38 (3H, m), 7.41-7.49(2H, m), 7.58 (2H, d, J = 8.3 Hz), 7.62-7.68 (2H, m), 7.78-7.81 (1H, m),8.28 (1H, d, J = 2.5 Hz), 8.78 (1H, d, J = 1.4 Hz), DMSO: 431 (M +H)⁺FAB 282 1.07-1.33 (2H, m), 1.42-1.54 (1H, m), 1.47-1.59 (2H, m),1.72-1.83 (2H, m), 2.62 (2H, dd, J = 7.6, 7.6 Hz), 2.78-2.93 (1H, m),2.93-3.10 (1H, m), 3.92-4.08 (1H, m), 4.08-4.24 (1H, m), 7.05-7.13 (2H,m), 7.20-7.28 (2H, m), 8.04 (1H, dd, J = 2.5, 2.1 Hz), 8.64 (1H, d, J =2.5 Hz), 8.92 (1H, d, J = 2.1 Hz), 13.62 (1H, br s), DMSO: 373 (M +H)⁺FAB 283 1.10-1.35 (2H, m), 1.46-1.62 (3H, m), 1.74-1.88 (2H, m), 2.74(2H, dd, J = 7.8, 7.8 Hz), 2.80-2.96 (1H, m), 2.96-3.12 (1H, m),3.94-4.08 (1H, m), 4.11-4.26 (1H, m), 7.18-7.32 (2H, m), 7.32-7.43 (2H,m), 8.05 (1H, dd, J = 2.1, 1.6 Hz), 8.65 (1H, d, J = 2.1 Hz), 8.91 (1H,d, J = 1.6 Hz), 13.62 (1H, br s), DMSO: 387 (M − H)⁻FAB 284 1.08-1.32(2H, m), 1.41-1.55 (1H, m), 1.48-1.60 (2H, m), 1.71-1.83 (2H, m), 2.62(2H, dd, J = 7.8, 7.8 Hz), 2.78-2.93 (1H, m), 2.93-3.09 (1H, m),3.94-4.08 (1H, m), 4.10-4.23 (1H, m), 7.25 (2H, d, J = 8.6 Hz), 7.33(2H, d, J = 8.0 Hz), 8.04 (1H, dd, J = 2.2, 1.6 Hz), 8.64 (1H, d, J =2.2 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.61 (1H, br s), DMSO: 389 (M +H)⁺FAB 285 1.06-1.32 (2H, m), 1.40-1.54 (1H, m), 1.47-1.60 (2H, m),1.70-1.84 (2H, m), 2.61 (2H, dd, J = 7.6, 7.6 Hz), 2.79-2.94 (1H, m),2.94-3.09 (1H, m), 3.92-4.08 (1H, m), 4.08-4.25 (1H, m), 7.19 (2H, d, J= 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz), 8.04 (1H, dd, J = 2.4, 1.2 Hz),8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.2 Hz), 13.60 (1H, br s),DMSO: 431 (M − H)⁻FAB 286 1.08-1.32 (2H, m), 1.42-1.58 (3H, m),1.70-1.84 (2H, m), 2.56 (2H, dd, J = 7.4, 7.4 Hz), 2.78-2.93 (1H, m),2.93-3.07 (1H, m), 3.72 (3H, s), 3.94-4.08 (1H, m), 4.08-4.23 (1H, m),6.84 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz), 8.04 (1H, dd, J =2.8, 1.6 Hz), 8.64 (1H, d, J = 2.8 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.60(1H, br s), DMSO: 385 (M + H)⁺FAB

TABLE 53 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 287 1.01-1.74 (11H,m), 2.58 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m),7.14-7.31 (5H, m), 8.04 (1H, t, J = 2.4 Hz), 8.64 (1H, d, J = 2.4 Hz),8.91 (1H, d, J = 1.6 Hz), 13.60 (1H, s), DMSO: 383 (M + H)⁺FAB 2881.08-1.34 (2H, m), 1.44-1.60 (3H, m), 1.73-1.86 (2H, m), 2.66 (2H, dd, J= 7.4, 7.4 Hz), 2.78-2.95 (1H, m), 2.95-3.12 (1H, m), 3.93-4.09 (1H, m),4.10-4.26 (1H, m), 7.08-7.18 (2H, m), 7.20-7.27 (1H, m), 7.27-7.36 (1H,m), 8.05 (1H, dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.91 (1H,d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 373 (M + H)⁺FAB 289 0.79-0.93(2H, m), 1.00-1.28 (10H, m), 1.35-1.48 (1H, m), 1.57-1.76 (7H, m),2.80-3.08 (2H, br), 3.96-4.22 (2H, br), 8.02-8.05 (1H, m), 8.62-8.66(1H, m), 8.89-8.93 (1H, m), 13.53-13.64 (1H, br), DMSO: 361 (M + H)⁺FAB290 1.13-1.32 (2H, m), 1.46-1.59 (1H, m), 1.54-1.62 (2H, m), 1.75-1.87(2H, m), 2.69 (2H, dd, J = 7.8, 7.8 Hz), 2.81-2.94 (1H, m), 2.94-3.10(1H, m), 3.94-4.10 (1H, m), 4.10-4.27 (1H, m), 7.29-7.38 (3H, m), 7.86(1H, ddd, J = 7.4, 7.4, 1.6 Hz), 7.93 (1H, d, J = 8.0 Hz), 8.01 (2H, d,J = 8.0 Hz), 8.05 (1H, dd, J = 2.8, 1.6 Hz), 8.62-8.68 (2H, m), 8.92(1H, d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 432 (M + H)⁺ESI 2911.08-1.32 (2H, m), 1.44-1.61 (3H, m), 1.77-1.83 (2H, br), 2.63 (2H, t, J= 7.6 Hz), 2.79-3.08 (2H, br), 3.95-4.23 (2H, br), 6.73 (1H, d, J = 16.0Hz), 7.14-7.22 (3H, m), 7.25-7.32 (2H, m), 7.64 (1H, d, J = 16.0 Hz),8.02-8.06 (1H, m), 8.40-8.44 (1H, m), 8.68-8.73 (1H, m), 12.55-12.63(1H, br), DMSO: 381 (M + H)⁺FAB 292 1.10-1.32 (2H, m), 1.45-1.60 (3H,m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 8.4 Hz), 2.80-3.10 (2H, m),3.95-4.24 (2H, m), 7.20-7.28 (2H, m), 7.36-7.40 (1H, m), 7.44 (1H, br),8.04 (1H, t, J = 2.0 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.6Hz), 13.60 (1H, s), DMSO: 435, 433 (M + H)⁺ESI 293 1.10-1.32 (2H, m),1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 7.6 Hz),2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.22 (1H, d, J = 7.2 Hz),7.33-7.52 (6H, m), 7.64-7.68 (1H, m), 8.04 (1H, dd, J = 1.2, 2.4 Hz),8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 2.0 Hz), 13.60 (1H, s), DMSO:431 (M + H)⁺ESI 294 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H,m), 2.71 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.29(1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 8.0 Hz), 7.55 (1H, d, J = 7.6 Hz),7.62 (1H, s), 7.67 (1H, t, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz),8.00-8.08 (2H, m), 8.16 (1H, s), 8.65 (1H, br), 8.91 (1H, br), 13.60(1H, s), DMSO: 456 (M + H)⁺FAB 295 1.07-1.34 (2H, m), 1.41-1.58 (1H, m),1.50-1.63 (2H, m), 1.70-1.85 (2H, m), 2.65 (2H, dd, J = 7.6, 7.6 Hz),2.78-2.94 (1H, m), 2.93-3.21 (1H, m), 3.92-4.09 (1H, m), 4.06-4.26 (1H,m), 7.26 (2H, d, J = 6.0 Hz), 8.04 (1H, dd, J = 2.8, 2.0 Hz), 8.45 (2H,br d, J = 4.4 Hz), 8.64 (1H, d, J = 2.8 Hz), 8.91 (1H, d, J = 2.0 Hz),DMSO: 356 (M + H)⁺FAB 296 1.08-1.35 (2H, m), 1.43-1.58 (1H, m),1.50-1.63 (2H, m), 1.71-1.86 (2H, m), 2.65 (2H, dd, J = 7.2, 7.2 Hz),2.77-2.96 (1H, m), 2.90-3.11 (1H, m), 3.90-4.08 (1H, m), 4.10-4.26 (1H,m), 7.31 (1H, dd, J = 8.0, 4.8 Hz), 7.65 (1H, d, J = 8.0 Hz), 8.04 (1H,dd, J = 2.4, 2.0 Hz), 8.40 (1H, br d, J = 3.2 Hz), 8.46 (1H, br s), 8.65(1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 354 (M − H)⁻FAB 2971.08-1.35 (2H, m), 1.43-1.60 (1H, m), 1.60-1.72 (2H, m), 1.74-1.85 (2H,m), 2.78 (2H, dd, J = 7.2, 7.2 Hz), 2.81-2.93 (1H, m), 2.94-3.08 (1H,m), 3.95-4.07 (1H, m), 4.11-4.24 (1H, m), 7.16-7.22 (1H, m), 7.27 (1H,d, J = 8.0 Hz), 7.69 (1H, ddd, J = 8.0, 8.0, 2.0 Hz), 8.04 (1H, dd, J =2.4, 2.0 Hz), 8.48 (1H, d, J = 4.4 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91(1H, d, J = 2.0 Hz), DMSO: 354 (M − H)⁻FAB 298 1.10-1.32 (2H, m),1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.69-2.75 (2H, m), 2.80-3.10 (2H,m), 3.95-4.24 (2H, m), 7.27-7.46 (3H, m), 7.80-7.99 (5H, m), 8.30 (1H,d, J = 2.8 Hz), 8.66 (1H, d, J = 4.4 Hz), 8.80 (1H, d, J = 1.6 Hz),DMSO: 432 (M + H)⁺FAB

TABLE 54 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 299 1.10-1.36 (2H,m), 1.45-1.60 (1H, m), 1.54-1.66 (2H, m), 1.74-1.87 (2H, m), 2.67 (2H,dd, J = 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.10 (1H, m), 3.92-4.10(1H, m), 4.10-4.25 (1H, m), 7.26 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J =8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.68 (2H, dd, J = 8.8, 5.2 Hz), 8.05(1H, dd, J = 3.2, 1.6 Hz), 8.65 (1H, d, J = 3.2 Hz), 8.92 (1H, d, J =1.6 Hz), 13.60 (1H, br s), DMSO: 449 (M + H)⁺FAB 300 1.11-1.36 (2H, m),1.46-1.59 (1H, m), 1.54-1.64 (2H, m), 1.74-1.86 (2H, m), 2.66 (2H, dd, J= 7.6, 7.6 Hz), 2.81-2.95 (1H, m), 2.95-3.10 (1H, m), 3.79 (3H, s),3.95-4.07 (1H, m), 4.12-4.25 (1H, m), 7.01 (2H, d, J = 8.8 Hz), 7.27(2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.58 (2H, d, J = 8.8 Hz),8.05 (1H, dd, J = 2.8, 2.0 Hz), 8.65 (1H, d, J = 2.8 Hz), 8.92 (1H, d, J= 2.0 Hz), 13.60 (1H, br s), DMSO: 461 (M + H)⁺FAB 301 1.10-1.36 (2H,m), 1.45-1.59 (1H, m), 1.55-1.66 (2H, m), 1.75-1.87 (2H, m), 2.69 (2H,dd, J = 7.2, 7.2 Hz), 2.80-2.94 (1H, m), 2.96-3.12 (1H, m), 3.93-4.10(1H, m), 4.10-4.27 (1H, m), 7.36 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J =8.4 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 8.05 (1H,dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.6Hz), 13.61 (1H, br s), DMSO: 456 (M + H)⁺FAB 302 1.10-1.36 (2H, m),1.45-1.58 (1H, m), 1.55-1.65 (2H, m), 1.71-1.88 (2H, m), 2.68 (2H, dd, J= 7.6, 7.6 Hz), 2.78-2.95 (1H, m), 2.95-3.12 (1H, m), 3.92-4.10 (1H, m),4.10-4.26 (1H, m), 7.10-7.22 (1H, m), 7.32 (2H, d, J = 8.0 Hz),7.42-7.54 (3H, m), 7.63 (2H, d, J = 8.0 Hz), 8.05 (1H, dd, J = 2.4, 2.0Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), 13.61 (1H, brs), DMSO: 449 (M + H)⁺FAB 303 1.11-1.35 (2H, m), 1.46-1.58 (1H, m),1.54-1.64 (2H, m), 1.75-1.86 (2H, m), 2.67 (2H, dd, J = 7.6, 7.6 Hz),2.80-2.95 (1H, m), 2.95-3.12 (1H, m), 3.82 (3H, s), 3.94-4.10 (1H, m),4.10-4.25 (1H, m), 6.91 (1H, ddd, J = 8.4, 2.4, 0.8 Hz), 7.14-7.18 (1H,m), 7.18-7.23 (1H, m), 7.30 (2H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 8.0,8.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 8.05 (1H, dd, J = 2.4, 2.0 Hz), 8.65(1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), 13.60 (1H, br s), DMSO:459 (M − H)⁻ESI 304 1.10-1.36 (2H, m), 1.47-1.58 (1H, m), 1.55-1.66 (2H,m), 1.74-1.88 (2H, m), 2.87 (2H, dd, J = 7.6, 7.6 Hz), 2.82-2.96 (1H,m), 2.96-3.13 (1H, m), 3.95-4.10 (1H, m), 4.10-4.26 (1H, m), 7.24-7.32(2H, m), 7.33 (2H, d, J = 8.4 Hz), 7.36-7.44 (1H, m), 7.44-7.50 (2H, m),7.48-7.55 (1H, m), 8.05 (1H, dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4Hz), 8.92 (1H, d, J = 1.6 Hz), 13.61 (1H, br s), DMSO: 449 (M + H)⁺FAB305 480 (M + H)⁺FAB 306 488 (M + Na)⁺ESI 307 490 (M + Na)⁺ESI 3081.12-1.29 (2H, m), 1.50-1.63 (9H, m), 1.78-1.81 (2H, br), 2.64-2.69 (2H,m), 2.86 (1H, br), 3.02 (1H, br), 3.23-3.38 (2H, m), 3.51-3.64 (2H, m),4.01 (1H, m), 4.17 (1H, m), 7.25-7.31 (4H, m), 7.80 (1H, m), 8.28 (1H,m), 8.80 (1H, m), DMSO: 464 (M − H)⁻FAB 309 1.15-1.28 (2H, m), 1.47-1.60(3H, m), 1.78-1.81 (2H, br), 2.65-2.69 (2H, br), 2.86 (1H, m), 3.02 (1H,m), 3.40-3.63 (8H, br), 4.01 (1H, m), 4.18 (1H, m), 7.28-7.34 (4H, m),7.80 (1H, m), 8.28 (1H, m), 8.80 (1H, m), DMSO: 468 (M + H)⁺FAB 310 452(M + H)⁺FAB 311 544 (M + H)⁺ESI 312 454 (M + H)⁺ESI 313 1.10-1.80 (16H,m), 2.27 (3H, s), 2.65-2.74 (2H, m), 2.80-3.10 (2H, m), 3.95-4.32 (4H,m), 6.42 (1H, d, J = 7.6 Hz), 6.56 (1H, d, J = 8.8 Hz), 7.36 (1H, t, J =8.0 Hz), 7.80 (1H, br), 8.27 (1H, d, J = 3.2 Hz), 8.79 (1H, br), DMSO:467 (M + H)⁺FAB 314 1.07-1.21 (2H, m), 1.27-1.51 (10H, m), 1.73-1.77(2H, br), 1.81-1.84 (2H, br) 2.83-2.89 (3H, br), 3.04 (1H, br),3.72-3.76 (2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.33 (1H, m), 7.58(1H, m), 7.68 (1H, m), 7.80 (1H, m), 7.86 (1H, m), 8.04 (1H, m), 8.08(1H, m), 8.28 (1H, m), 8.79 (1H, m), DMSO: 503 (M + H)⁺FAB

TABLE 55 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 315 1.00-1.82 (16H,m), 2.77-3.08 (4H, m), 3.95-4.23 (2H, m), 4.53 (2H, d, J = 12.0 Hz),7.10-7.23 (2H, m), 7.42-7.58 (2H, m), 7.66 (1H, d, J = 7.5 Hz), 7.81(1H, s), 7.99 (1H, d, J = 8.5 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.80 (1H,s), DMSO: 503 (M + H)⁺FAB 316 1.08-1.23 (2H, m), 1.26-1.32 (2H, m),1.47-1.57 (3H, m), 1.73-1.77 (2H, m), 2.37-2.41 (2H, m) 2.61-2.67 (4H,br), 2.87 (1H, m), 2.03 (1H, m), 3.27-3.33 (4H, br), 4.02 (1H, br), 4.18(1H, br), 7.37 (1H, m), 7.59 (1H, m), 7.70 (1H, m), 7.81 (1H, m), 7.87(1H, m), 8.06-8.11 (2H, m), 8.29 (1H, m), 8.80 (1H, m), DMSO: 526 (M +Na)⁺ESI 317 1.07-1.21 (2H, m), 1.27-1.51 (10H, m), 1.73-1.77 (2H, br),1.82-1.85 (2H, br) 2.67-2.73 (2H, br), 2.87 (1H, m), 3.02 (1H, br),3.28-3.39 (2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.09 (1H, m), 7.41(1H, m), 7.46-7.52 (2H, m), 7.55 (1H, m), 7.82 (1H, m), 7.86 (1H, m),8.08 (1H, m), 8.29 (1H, m), 8.80 (1H, m), DMSO: 524 (M + Na)⁺FAB 3181.10-1.30 (2H, m), 1.44-1.62 (3H, m), 1.75-1.83 (2H, m), 2.70 (2H, t, J= 7.3 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.47-7.74 (5H, m), 8.02(1H, t, J = 2.5 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H,d, J = 2.0 Hz), DMSO: 379 (M + H)⁺FAB 319 1.10-1.30 (2H, m), 1.45-1.59(3H, m), 1.80 (2H, d, J = 12.2 Hz), 2.63 (2H, t, J = 7.4 Hz), 2.88 (1H,t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 3.31-3.38 (2H, m), 3.50-3.55(2H, m), 4.02 (1H, d, J = 12.2 Hz), 4.18 (1H, d, J = 12.2 Hz), 7.15-7.31(5H, m), 8.01 (1H, t, J = 2.4 Hz), 8.55 (1H, s), 8.69 (1H, t, J = 5.6Hz), 8.88 (1H, s), DMSO: 398 (M + H)⁺FAB 320 1.10-1.30 (2H, m),1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 7.4 Hz),2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.15-7.31 (5H, m), 7.67 (1H, s),8.01 (1H, t, J = 1.9 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89(1H, d, J = 2.0 Hz), DMSO: 354 (M + H)⁺FAB 321 1.10-1.30 (2H, m),1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.60 (2H, t, J = 7.3 Hz),2.80-3.10 (2H, m), 3.74 (3H, s), 3.95-4.24 (2H, m), 6.70-6.84 (3H, m),7.13-7.24 (1H, m), 7.66 (1H, s), 8.01 (1H, br), 8.18 (1H, s), 8.55 (1H,d, J = 2.4 Hz), 8.89 (1H, br), DMSO: 384 (M + H)⁺FAB 322 1.10-1.30 (2H,m), 1.44-1.60 (3H, m), 1.75-1.83 (2H, m), 2.65 (2H, t, J = 7.3 Hz),2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 6.96-7.10 (3H, m), 7.29-7.36 (1H,m), 7.66 (1H, s), 8.01 (1H, t, J = 2.5 Hz), 8.17 (1H, s), 8.55 (1H, d, J= 2.4 Hz), 8.89 (1H, d, J = 1.9 Hz), DMSO: 372 (M + H)⁺FAB 323 1.10-1.34(2H, m), 1.50-1.64 (3H, m), 1.75-1.88 (2H, m), 2.80-3.10 (4H, m),3.95-4.24 (2H, m), 7.41 (1H, dt, J = 1.0, 7.4 Hz), 7.51 (1H, d, J = 7.8Hz), 7.62-7.70 (2H, m), 7.79 (1H, dd, J = 1.5, 7.8 Hz), 8.02 (1H, t, J =2.0 Hz), 8.17 (1H, s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0Hz), DMSO: 379 (M + H)⁺FAB 324 1.10-1.34 (2H, m), 1.45-1.64 (3H, m),1.75-1.88 (2H, m), 2.66 (2H, t, J = 7.8 Hz), 2.80-3.10 (2H, m),3.95-4.24 (2H, m), 7.26-7.40 (3H, m), 7.64-7.75 (3H, m), 7.92 (1H, s),8.01 (1H, br), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J =2.4 Hz), DMSO: 397 (M + H)⁺FAB 325 1.10-1.34 (2H, m), 1.45-1.64 (3H, m),1.75-1.85 (2H, m), 2.66 (2H, t, J = 7.3 Hz), 2.80-3.10 (8H, m),3.95-4.24 (2H, m), 7.16-7.37 (4H, m), 7.66 (1H, s), 8.01 (1H, br), 8.17(1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.4 Hz), DMSO: 425(M + H)⁺FAB 326 0.79-0.93 (2H, m), 1.02-1.30 (10H, m), 1.37-1.49 (1H, m)1.57-1.77 (7H, m), 2.81-2.92 (1H, br), 2.96-3.08 (1H, br), 3.94-4.05(1H, br), 4.10-4.21 (1H, br), 7.63-7.70 (1H, br), 8.00 (1H, dd, J = 3.0Hz, 2.4 Hz), 8.13-8.21 (1H, m), 8.55 (1H, d, J = 3.0 Hz),, 8.88 (1H, d,J = 2.4 Hz), DMSO: 360 (M + H)⁺FAB 327 1.10-1.30 (2H, m), 1.45-1.60 (3H,m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m),3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.16-7.34 (4H,m), 8.02 (1H, t, J = 2.4 Hz), 8.55 (1H, br), 8.69 (1H, t, J = 5.6 Hz),8.87 (1H, s), DMSO: 432 (M + H)⁺FAB

TABLE 56 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 328 1.10-1.30 (2H,m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.60 (2H, t, J = 7.6 Hz),2.80-3.10 (2H, m), 3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.74 (3H, s),3.95-4.24 (2H, m), 6.71-6.82 (3H, m), 7.19 (1H, t, J = 7.2 Hz), 8.01(1H, br), 8.55 (1H, br), 8.68 (1H, t, J = 6.0 Hz), 8.87 (1H, br), DMSO:428 (M + H)⁺FAB 329 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H,m), 2.65 (2H, t, J = 8.4 Hz), 2.80-3.10 (2H, m), 3.30-3.38 (2H, m),3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.05-7.10 (3H, m), 7.30-7.35 (1H,m), 8.00 (1H, t, J = 2.4 Hz), 8.55 (1H, br), 8.68 (1H, t, J = 5.6 Hz),8.87 (1H, br), DMSO: 416 (M + H)⁺FAB 330 1.10-1.30 (2H, m), 1.45-1.62(3H, m), 1.75-1.85 (2H, m), 2.70 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m),3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.50 (1H, t, J= 8.0 Hz), 7.56-7.74 (3H, m), 8.02 (1H, t, J = 2.0 Hz), 8.55 (1H, d, J =2.0 Hz), 8.69 (1H, t, J = 6.0 Hz), 8.87 (1H, br), DMSO: 423 (M + H)⁺FAB331 1.10-1.34 (2H, m), 1.50-1.64 (3H, m), 1.75-1.89 (2H, m), 2.84 (2H,t, J = 8.0 Hz), 2.84-3.11 (2H, m), 3.31-3.38 (2H, m), 3.49-3.55 (2H, m),3.95-4.25 (2H, m), 7.40 (1H, dt, J = 0.8, 7.6 Hz), 7.52 (1H, d, J = 7.2Hz), 7.65 (1H, dt, J = 1.6, 7.6 Hz), 7.79 (1H, dd, J = 1.2, 8.0 Hz),8.04 (1H, t, J = 2.0 Hz), 8.55 (1H, d, J = 2.4 Hz), 8.69 (1H, t, J = 5.6Hz), 8.87 (1H, d, J = 1.6 Hz), DMSO: 423 (M + H)⁺FAB 332 462 (M + H)⁺FAB333 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.80 (2H, d, J = 12.0 Hz),2.37 (2H, t, J = 7.2 Hz), 2.63 (2H, t, J = 7.2 Hz), 2.87 (1H, t, J =12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 3.41-3.49 (2H, m), 4.01 (1H, d, J =12.2 Hz), 4.18 (1H, d, J = 12.2 Hz), 6.83 (1H, s), 7.15-7.31 (5H, m),7.36 (1H, s), 7.99 (1H, t, J = 2.4 Hz), 8.55 (1H, d, J = 3.2 Hz), 8.76(1H, t, J = 5.6 Hz), 8.85 (1H, t, J = 2.0 Hz), DMSO: 425 (M + H)⁺FAB 3341.08-1.32 (2H, m), 1.45-1.60 (3H, m), 1.74-1.86 (2H, m), 2.66 (2H, dd, J= 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.11 (1H, m), 3.95-4.08 (1H, m),4.11-4.25 (1H, m), 7.09-7.17 (2H, m), 7.20-7.28 (1H, m), 7.28-7.36 (1H,m), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.18 (1H, br s),8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 372 (M +H)⁺FAB 335 1.08-1.32 (2H, m), 1.44-1.61 (3H, m), 1.77-1.83 (2H, br),2.63 (2H, t, J = 7.6 Hz), 2.79-3.08 (2H, br), 3.95-4.23 (2H, br), 6.73(1H, d, J = 16.0 Hz), 7.14-7.22 (3H, m), 7.25-7.32 (2H, m), 7.64 (1H, d,J = 16.0 Hz), 8.02-8.06 (1H, m), 8.40-8.44 (1H, m), 8.68-8.73 (1H, m),12.55-12.63 (1H, br), DMSO: 380 (M + H)⁺FAB 336 1.09-1.31 (2H, m),1.43-1.56 (1H, m), 1.53-1.64 (2H, m), 1.71-1.86 (2H, m), 2.67 (2H, dd, J= 8.0, 8.0 Hz), 2.79-2.96 (1H, m), 2.92-3.11 (1H, m), 3.93-4.10 (1H, m),4.08-4.24 (1H, m), 7.31 (2H, d, J = 5.2 Hz), 7.67 (1H, s), 8.01 (1H, dd,J = 2.4, 1.6 Hz), 8.19 (1H, s), 8.49 (2H, br s), 8.56 (1H, d, J = 2.4Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 355 (M + H)⁺ESI 337 1.08-1.32 (2H,m), 1.43-1.57 (1H, m), 1.52-1.63 (2H, m), 1.72-1.86 (2H, m), 2.66 (2H,dd, J = 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.11 (1H, m), 3.93-4.08(1H, m), 4.10-4.25 (1H, m), 7.33 (1H, dd, J = 7.6, 4.8 Hz), 7.62-7.72(2H, m), 8.01 (1H, dd, J = 2.4, 1.6 Hz), 8.19 (1H, br s), 8.41 (1H, brs), 8.47 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz),DMSO: 355 (M + H)⁺ESI 338 1.10-1.33 (2H, m), 1.45-1.59 (1H, m),1.54-1.65 (2H, m), 1.75-1.87 (2H, m), 2.67 (2H, dd, J = 7.6, 7.6 Hz),2.81-2.95 (1H, m), 2.96-3.10 (1H, m), 3.92-4.08 (1H, m), 4.11-4.25 (1H,m), 7.27 (2H, t, J = 8.8 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J =8.4 Hz), 7.63-7.72 (3H, m), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.19 (1H, brs), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 448 (M +H)⁺FAB 339 1.10-1.33 (2H, m), 1.47-1.63 (1H, m), 1.53-1.65 (2H, m),1.76-1.88 (2H, m), 2.66 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.96 (1H, m),2.96-3.11 (1H, m), 3.79 (3H, s), 3.96-4.07 (1H, m), 4.12-4.25 (1H, m),7.01 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.4Hz), 7.58 (2H, d, J = 8.4 Hz), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4,2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0Hz), DMSO: 458 (M + H)⁺FAB

TABLE 57 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 340 1.10-1.32 (2H,m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 8.0 Hz),2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.23 (1H, d, J = 7.2 Hz),7.33-7.52 (6H, m), 7.64-7.71 (2H, m), 8.02 (1H, t, J = 2.0 Hz), 8.19(1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 430(M + H)⁺FAB 341 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m),2.71 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.29(1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 7.6 Hz), 7.55 (1H, d, J = 7.2 Hz),7.60-7.73 (3H, m), 7.82 (1H, d, J = 7.2 Hz), 8.00-8.08 (2H, m), 8.16(1H, s), 8.20 (1H, s), 8.65 (1H, br), 8.91 (1H, br), DMSO: 455 (M +H)⁺FAB 342 1.06-1.30 (2H, m), 1.43-1.56 (1H, m), 1.51-1.61 (2H, m), 1.69(2H, q, J = 6.4 Hz), 1.74-1.85 (2H, m), 2.63 (2H, dd, J = 7.6, 7.6 Hz),2.80-2.94 (1H, m), 2.94-3.10 (2H, m), 3.33 (2H, td, J = 6.4, 6.4 Hz),3.47 (2H, t, J = 6.4 Hz), 3.93-4.09 (1H, m), 4.09-4.24 (1H, m),7.13-7.24 (3H, m), 7.24-7.31 (2H, m), 7.99 (1H, dd, J = 2.4, 1.6 Hz),8.54 (1H, d, J = 2.4 Hz), 8.67 (1H, br t, J = 5.2 Hz), 8.85 (1H, d, J =1.6 Hz), DMSO: 412 (M + H)⁺FAB 343 1.08-1.31 (2H, m), 1.44-1.56 (1H, m),1.52-1.61 (2H, m), 1.74-1.86 (2H, m), 1.82-1.93 (2H, m), 2.63 (2H, dd, J= 7.2, 7.2 Hz), 2.72 (6H, s), 2.80-2.93 (1H, m), 2.98-3.09 (3H, m), 3.34(2H, td, J = 6.4, 6.4 Hz), 3.94-4.07 (1H, m), 4.10-4.24 (1H, m),7.13-7.24 (3H, m), 7.24-7.32 (2H, m), 8.00 (1H, dd, J = 2.4, 1.6 Hz),8.57 (1H, d, J = 2.4 Hz), 8.85 (1H, br t, J = 5.6 Hz), 8.88 (1H, d, J =1.6 Hz), DMSO: 439 (M + H)⁺FAB 344 1.09-1.34 (2H, m), 1.45-1.60 (1H, m),1.55-1.66 (2H, m), 1.75-1.87 (2H, m), 2.70 (2H, dd, J = 7.6, 7.6 Hz),2.80-2.96 (1H, m), 2.96-3.11 (1H, m), 3.94-4.09 (1H, m), 4.10-4.26 (1H,m), 7.37 (2H, d, J = 8.4 Hz), 7.68 (1H, br s), 7.69 (2H, d, J = 8.4 Hz),7.87 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.02 (1H, dd, J =2.4, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J= 2.0 Hz), DMSO: 455 (M + H)⁺FAB 345 1.10-1.34 (2H, m), 1.46-1.60 (1H,m), 1.54-1.66 (2H, m), 1.75-1.89 (2H, m), 2.68 (2H, dd, J = 7.6, 7.6Hz), 2.80-2.96 (1H, m), 2.96-3.12 (1H, m), 3.95-4.09 (1H, m), 4.11-4.26(1H, m), 7.13-7.21 (1H, m), 7.33 (2H, d, J = 8.0 Hz), 7.45-7.52 (3H, m),7.63 (2H, d, J = 8.0 Hz), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4, 2.0Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0Hz), DMSO: 448 (M + H)⁺FAB 346 1.10-1.35 (2H, m), 1.48-1.61 (1H, m),1.56-1.66 (2H, m), 1.76-1.90 (2H, m), 2.69 (2H, dd, J = 8.0, 8.0 Hz),2.81-2.97 (1H, m), 2.97-3.13 (1H, m), 3.95-4.10 (1H, m), 4.10-4.26 (1H,m), 7.25-7.32 (2H, m), 7.33 (2H, d, J = 8.0 Hz), 7.36-7.44 (1H, m),7.44-7.50 (2H, m), 7.48-7.56 (1H, m), 7.67 (1H, br s), 8.02 (1H, dd, J =2.8, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J= 2.0 Hz), DMSO: 448 (M + H)⁺FAB 347 1.08-1.31 (2H, m), 1.43-1.55 (1H,m), 1.50-1.61 (2H, m), 1.72-1.85 (2H, m), 2.63 (2H, dd, J = 7.8, 7.8Hz), 2.80-2.93 (1H, m), 2.90 (2H, t, J = 6.8 Hz), 2.96-3.09 (1H, m),3.56 (2H, td, J = 6.8, 6.8 Hz), 3.93-4.08 (1H, m), 4.08-4.23 (1H, m),7.14-7.24 (3H, m), 7.24-7.31 (2H, m), 7.33 (2H, d, J = 5.6 Hz), 7.95(1H, dd, J = 2.8, 1.6 Hz), 8.50 (2H, br s), 8.55 (1H, d, J = 2.8 Hz),8.81 (1H, d, J = 1.6 Hz), 8.81 (1H, t, J = 6.0 Hz), DMSO: 459 (M +H)⁺FAB 348 1.08-1.31 (2H, m), 1.43-1.57 (1H, m), 1.50-1.62 (2H, m),1.73-1.86 (2H, m), 2.63 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.93 (1H, m),2.89 (2H, t, J = 6.8 Hz), 2.96-3.09 (1H, m), 3.54 (2H, td, J = 6.8, 6.8Hz), 3.94-4.09 (1H, m), 4.09-4.25 (1H, m), 7.13-7.25 (3H, m), 7.25-7.32(2H, m), 7.35 (1H, dd, J = 7.6, 4.8 Hz), 7.71 (1H, d, J = 7.6 Hz),7.92-7.97 (1H, m), 8.44 (1H, br s), 8.49 (1H, br s), 8.52-8.59 (1H, m),8.77-8.85 (2H, m), DMSO: 459 (M + H)⁺FAB 349 1.10-1.32 (2H, m),1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.69-2.78 (2H, m), 2.80-3.10 (2H,m), 3.95-4.24 (2H, m), 7.27-7.46 (3H, m), 7.66 (1H, s), 7.83-8.03 (5H,m), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.66 (1H, br), 8.89 (1H, d,J = 1.2 Hz), DMSO: 431 (M + H)⁺FAB 350 425 (M + H)⁺FAB 351 1.05-1.85(17H, m), 2.67 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.70-3.80 (1H,m), 3.95-4.24 (2H, m), 7.33-7.37 (2H, m), 7.62-7.70 (3H, m), 8.01 (1H,t, J = 2.0 Hz), 8.13 (1H, d, J = 7.6 Hz), 8.17 (1H, s), 8.55 (1H, d, J =2.8 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 479 (M + H)⁺FAB

TABLE 58 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 352 411 (M + H)⁺FAB353 1.08-1.32 (2H, m), 1.43-1.58 (1H, m), 1.52-1.64 (2H, m), 1.72-1.87(2H, m), 2.68 (2H, dd, J = 7.8, 7.8 Hz), 2.78-2.95 (1H, m), 2.97-3.12(1H, m), 3.93-4.09 (1H, m), 4.10-4.25 (1H, m), 7.26 (1H, br s), 7.29(2H, d, J = 8.0 Hz), 7.67 (1H, br s), 7.79 (2H, d, J = 8.0 Hz), 7.89(1H, br s), 8.01 (1H, dd, J = 2.4, 1.2 Hz), 8.18 (1H, br s), 8.55 (1H,d, J = 2.4 Hz), 8.89 (1H, d, J = 1.2 Hz), DMSO: 397 (M + H)⁺FAB 3541.08-1.33 (2H, m), 1.44-1.58 (1H, m), 1.52-1.64 (2H, m), 1.73-1.88 (2H,m), 2.67 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.96 (1H, m), 2.92 (3H, s),2.95 (3H, s), 2.96-3.12 (1H, m), 3.92-4.08 (1H, m), 4.09-4.25 (1H, m),7.27 (2H, d, J = 7.6 Hz), 7.32 (2H, d, J = 7.6 Hz), 7.67 (1H, br s),8.01 (1H, dd, J = 2.4, 1.6 Hz), 8.18 (1H, br s), 8.56 (1H, d, J = 2.4Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 425 (M + H)⁺FAB 355 1.11-1.31 (2H,m), 1.40-1.66 (9H, m), 1.74-1.86 (2H, br), 2.64-2.69 (2H, m), 2.86 (1H,br), 3.02 (1H, br), 3.23-3.38 (2H, m), 3.51-3.64 (2H, m), 4.01 (1H, m),4.17 (1H, m), 7.15-7.20 (2H, m), 7.30-7.37 (2H, m), 7.67 (1H, s), 8.01(1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 465 (M + H)⁺ESI356 1.21-1.36 (2H, m), 1.54-1.59 (3H, m), 1.78-1.82 (2H, br), 2.64-2.69(2H, br), 2.87 (1H, m), 3.03 (1H, m), 3.37-3.69 (8H, br), 3.99 (1H, m),4.16 (1H, m), 7.15-7.20 (2H, m), 7.30-7.37 (2H, m), 7.67 (1H, s), 8.01(1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 467 (M + H)⁺ESI357 1.15-1.28 (2H, m), 1.44-1.62 (9H, m), 1.79-1.83 (2H, br), 2.65-2.68(2H, m), 2.88 (1H, br), 3.03 (1H, br), 3.24-3.37 (2H, br), 3.47-3.62(2H, m), 4.01 (1H, m), 4.18 (1H, m), 7.26-7.30 (4H, m), 7.67 (1H, s),8.02 (1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 465 (M +H)⁺FAB 358 1.13-1.28 (2H, m), 1.48-1.61 (3H, m), 1.79-1.82 (2H, br),2.65-2.69 (2H, br), 2.88 (1H, m), 3.04 (1H, m), 3.34-3.65 (8H, br), 4.01(1H, m), 4.18 (1H, m), 7.15-7.20 (2H, m), 7.28-7.34 (4H, m), 7.66 (1H,s), 8.01 (1H, m), 8.17 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 467(M + H)⁺FAB 359 1.16-1.25 (2H, m), 1.51-1.61 (3H, m), 1.79-1.88 (6H,br), 2.65-2.69 (2H, m), 2.87 (1H, br), 3.03 (1H, br), 3.31-3.38 (2H,br), 3.44-3.47 (2H, m), 4.01 (1H, m), 4.18 (1H, m), 7.29-7.36 (4H, m),7.68 (1H, s), 8.01 (1H, m), 8.19 (1H, s), 8.55 (1H, m), 8.89 (1H, m),DMSO: 451 (M + H)⁺ESI 360 1.03-1.31 (8H, m), 1.46-1.66 (3H, m),1.78-1.83 (2H, br), 2.64-2.69 (2H, m), 2.87 (1H, br), 3.03 (1H, br),3.14-3.24 (2H, br), 3.35-3.49 (2H, m), 4.03 (1H, m), 4.18 (1H, m),7.12-7.18 (2H, m), 7.27-7.37 (2H, m), 7.68 (1H, s), 8.02 (1H, m), 8.19(1H, s), 8.56 (1H, m), 8.89 (1H, m), DMSO: 453 (M + H)⁺ESI 361 1.13-1.30(2H, m), 1.48-1.61 (3H, m), 1.78-1.83 (2H, br), 2.65-2.71 (2H, m), 2.87(1H, br), 3.03 (1H, br), 3.92-3.98 (2H, m), 4.00 (1H, m), 4.18 (1H, m),4.37-4.43 (2H, m), 7.38-7.41 (2H, m), 7.66-7.70 (2H, m), 7.73 (1H, s),8.01 (1H, m), 8.19 (1H, s), 8.56 (1H, m), 8.89 (1H, m), DMSO: 423 (M +H)⁺API 362 1.04-1.37 (8H, m), 1.45-1.68 (3H, m), 1.83 (2H, d, J = 12.8Hz), 2.69 (2H, t, J = 7.3 Hz), 2.86 (1H, t, J = 12.1 Hz), 2.99 (1H, t, J= 12.1 Hz), 3.28 (2H, br), 3.53 (2H, br), 4.15-4.34 (2H, m), 7.20 (2H,d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.01 (1H, s), 8.59 (1H, s),8.89 (1H, s)CDCl3: 453 (M + H)⁺ESI 363 1.18-1.36 (2H, m), 1.44-1.68 (3H,m), 1.76-2.12 (6H, m), 2.69 (2H, t, J = 7.5 Hz), 2.84 (2H, t, J = 11.9Hz), 2.98 (2H, t, J = 11.9 Hz), 4.25 (4H, br), 6.02 (1H, br), 6.73 (1H,br), 7.20 (2H, d, J = 7.9 Hz), 7.45 (2H, d, J = 7.9 Hz), 7.98 (1H, s),8.57 (1H, s), 8.85 (1H, s)CDCl3: 451 (M + H)⁺ESI

TABLE 59 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 364 1.18-1.36 (2H,m), 1.44-1.70 (3H, m), 1.77-1.92 (2H, m), 2.72 (2H, t, J = 7.5 Hz), 2.85(2H, t, J = 11.4 Hz), 2.99 (2H, t, J = 11.4 Hz), 4.08 (2H, t, J = 9.6Hz), 4.26 (2H, br), 4.47 (2H, t, J = 9.6 Hz), 7.25 (2H, d, J = 7.8 Hz),7.91 (2H, d, J = 7.8 Hz), 7.94-7.99 (1H, m), 8.58 (1H, d, J = 2.4 Hz),8.83 (1H, d, J = 2.4 Hz)CDCl3: 423 (M + H)⁺ESI 365 1.03 (2H, d, J = 6.2Hz), 1.12-1.30 (2H, m), 1.48-1.62 (3H, m), 1.80 (2H, d, J = 12.8 Hz),2.68 (2H, t, J = 7.4 Hz), 2.87 (1H, t, J = 12.8 Hz), 3.03 (1H, t, J =12.8 Hz), 3.38-3.80 (6H, m), 4.01 (1H, d, J = 12.8 Hz), 4.17 (1H, d, J =12.8 Hz), 6.65-6.68 (1H, m), 6.84 (1H, d, J = 8.4 Hz), 7.23-7.39 (4H,m), 7.53-7.57 (1H, m), 7.66 (1H, s), 8.00-8.02 (1H, m), 8.11-8.13 (1H,m), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.88 (1H, d, J = 2.0 Hz),DMSO: 543 (M + H)⁺FAB 366 1.03 (2H, d, J = 6.2 Hz), 1.12-1.30 (2H, m),1.48-1.62 (3H, m), 1.80 (2H, d, J = 12.4 Hz), 2.68 (2H, t, J = 7.4 Hz),2.87 (1H, t, J = 12.4 Hz), 3.03 (1H, t, J = 12.4 Hz), 3.10-3.28 (3H, m),3.40-3.83 (3H, m), 4.02 (1H, d, J = 12.4 Hz), 4.18 (1H, d, J = 12.4 Hz),6.80 (1H, t, J = 7.6 Hz), 6.95 (2H, d, J = 7.6 Hz), 7.20-7.40 (6H, m),7.66 (1H, s), 8.00 (1H, t, J = 2.4 Hz), 8.18 (1H, s), 8.55 (1H, d, J =2.4 Hz), 8.88 (1H, d, J = 2.0 Hz), DMSO: 542 (M + H)⁺FAB 367 1.12-1.32(2H, m), 1.48-1.63 (3H, m), 1.82 (2H, d, J = 12.4 Hz), 2.68 (2H, t, J =7.2 Hz), 2.88 (1H, t, J = 12.4 Hz), 3.04 (1H, t, J = 12.4 Hz), 3.40-3.75(8H, m), 4.02 (1H, d, J = 12.4 Hz), 4.18 (1H, d, J = 12.4 Hz), 6.65-6.68(1H, m), 6.84 (1H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.36 (2H,d, J = 8.0 Hz), 7.53-7.57 (1H, m), 7.66 (1H, s), 8.01 (1H, d, J = 2.4Hz), 8.11-8.13 (1H, m), 8.18 (1H, s), 8.55 (1H, d, J = 2.8 Hz), 8.89(1H, d, J = 2.0 Hz), DMSO: 543 (M + H)⁺FAB 368 1.11-1.31 (2H, m),1.48-1.63 (3H, m), 1.81 (2H, d, J = 12.2 Hz), 2.68 (2H, t, J = 7.2 Hz),2.88 (1H, t, J = 12.8 Hz), 3.04 (1H, t, J = 12.8 Hz), 3.10-3.25 (4H, m),3.42-3.81 (4H, m), 4.02 (1H, d, J = 12.8 Hz), 4.18 (1H, d, J = 12.8 Hz),6.81 (1H, t, J = 7.2 Hz), 6.95 (2H, d, J = 8.4 Hz), 7.21-7.37 (6H, m),7.66 (1H, s), 8.01 (1H, s), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.88(1H, s), DMSO: 542 (M + H)⁺FAB 369 1.19-1.23 (2H, m), 1.52-1.62 (3H, m),1.78-1.85 (2H, m), 2.70 (2H, d, J = 7.8 Hz), 2.88 (1H, t, J = 11.9 Hz),3.03 (1H, t, J = 10.7 Hz), 3.52 (2H, dd, J = 5.4, 5.2 Hz), 3.59 (1H, dd,J = 5.3, 5.3 Hz), 4.02 (1H, m), 4.18 (1H, m), 4.48 (1H, t, J = 5.2 Hz),4.60 (1H, t, J = 5.2 Hz), 7.35-7.38 (2H, m), 7.68-7.69 (2H, m),7.72-7.75 (1H, m), 8.02-8.07 (1H, m), 8.18-8.23 (1H, m), 8.56-8.59 (1H,m), 8.63-8.68 (1H, m), 8.89-8.91 (1H, m), DMSO: 443 (M + H)⁺FAB 3701.13-1.33 (2H, m), 1.52-1.63 (3H, m), 1.75-1.85 (2H, m), 2.68 (2H, d, J= 7.8 Hz), 2.88 (1H, t, J = 10.0 Hz), 3.03 (1H, t, J = 10.0 Hz),3.30-3.35 (2H, m), 3.46-3.54 (2H, m), 4.15 (1H, d, J = 17.2 Hz), 4.18(1H, d, J = 16.0 Hz), 7.33-7.39 (2H, m), 7.62-7.72 (3H, m), 8.00-8.01(1H, m), 8.16-8.18 (1H, m), 8.35-8.29 (1H, m), 8.55 (1H, d, J = 3.4 Hz),8.89 (1H, d, J = 2.2 Hz), DMSO: 441 (M + H)⁺ESI 371 1.21-1.35 (2H, m),1.48 (9H, s), 1.48-1.60 (1H, m), 1.61-1.69 (2H, m), 1.79-1.87 (2H, m),2.71 (2H, dd, J = 6.0, 6.0 Hz), 2.86 (1H, t, J = 9.6 Hz), 3.00 (1H, t, J= 9.6 Hz), 4.18-4.33 (2H, m), 5.76 (1H, br), 5.93 (1H, s), 6.28 (1H,br), 7.27-7.35 (2H, m), 7.45-7.50 (1H, m), 7.61 (1H, s), 7.96 (1H, s),8.58 (1H, s), 8.84 (1H, s)CDCl3: 454 (M + H)⁺ESI 372 1.27 (6H, d, J =4.8 Hz), 1.61-1.69 (2H, m), 1.72-1.88 (5H, m), 2.71 (2H, t, J = 6.0, 6.0Hz), 2.86 (1H, t, J = 9.0 Hz), 3.00 (1H, t, J = 9.0 Hz), 4.17-4.36 (3H,m), 5.81 (1H, br), 5.95 (1H, br), 6.54 (1H, br), 7.21-7.39 (2H, m), 7.52(1H, d, J = 6.0 Hz), 7.63 (1H, s), 7.97 (1H, s), 8.61 (1H, s), 8.89 (1H,s)CDCl3: 439 (M + H)⁺ESI 373 1.10-1.31 (2H, m), 1.47-1.62 (3H, m),1.78-1.83 (2H, m), 2.39-2.51 (2H, m), 2.66-2.69 (2H, m), 2.82-2.92 (1H,br), 2.98-3.10 (1H, br), 3.65-3.73 (2H, br), 3.89 (2H, t, J = 13.1 Hz),3.98-4.22 (2H, m), 7.31 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz),7.63-7.69 (1H, br), 8.00-8.02 (1H, m), 8.15-8.21 (1H, br), 8.55-8.56(1H, m), 8.88-8.89 (1H, m), DMSO: 487 (M + H)⁺FAB

TABLE 60 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 374 1.10-1.31 (2H,m), 1.47-1.59 (3H, m), 1.77-1.83 (2H, m), 2.56 (2H, t, J = 7.5 Hz),2.82-3.08 (2H, m), 3.99-4.21 (2H, m), 5.77-5.82 (2H, br), 6.75 (1H, d, J= 7.5 Hz), 7.11 (1H, t, J = 7.5 Hz), 7.17-7.20 (1H, m), 7.25-7.27 (1H,br), 7.65-7.70 (1H, br), 8.00-8.03 (1H, m), 8.15-8.21 (1H, br),8.40-8.45 (1H, br), 8.54-8.56 (1H, m), 8.88-8.90 (1H, m), DMSO: 412 (M +H)⁺FAB 375 1.10-1.30 (2H, m), 1.46-1.60 (3H, m), 1.76-1.90 (6H, m), 2.57(2H, t, J = 7.4 Hz), 2.82-3.10 (2H, m), 3.32-3.39 (4H, m), 3.97-4.23(2H, m), 6.77 (1H, d, J = 7.8), 7.12 (1H, t, J = 7.8 Hz), 7.30-7.38 (2H,m), 7.64-7.68 (1H, br), 7.99-8.02 (2H, m), 8.16-8.21 (1H, br), 8.54-8.56(1H, m), 8.88-8.90 (1H, m), DMSO: 466 (M + H)⁺FAB 376 1.12-1.30 (2H, m),1.47-1.63 (3H, m), 1.77-1.85 (2H, m), 2.39-2.52 (2H, m), 2.69 (2H, t, J= 7.8 Hz), 2.83-3.08 (2H, m), 3.63-3.75 (2H, m), 3.83-3.94 (2H, m),3.97-4.24 (2H, m), 7.33-7.41 (4H, m), 7.66-7.70 (1H, br), 8.03-8.05 (1H,m), 8.18-8.22 (1H, br), 8.57 (1H, d, J = 2.4 Hz), 8.90 (1H, d, J = 1.7Hz), DMSO: 487 (M + H)⁺FAB 377 1.18-1.38 (2H, m), 1.48-1.71 (3H, m),1.78-1.89 (2H, m), 2.14-2.32 (2H, m), 2.71 (2H, t, J = 7.5 Hz),2.80-3.24 (6H, m), 3.57-3.83 (2H, m), 4.26 (2H, dd, J = 7.0 Hz), 5.80(1H, br), 6.51 (1H, br), 7.09 (1H, d, J = 7.5 Hz), 7.22-7.53 (7H, m),7.60 (1H, d, J = 8.2 Hz), 7.80-7.87 (1H, m), 8.05 (1H, dd, J = 2.0, 2.0Hz), 8.16-8.25 (1H, m), 8.60 (1H, s), 8.96 (1H, s), DMSO: 593 (M +H)⁺ESI 378 1.00-1.80 (16H, m), 2.27 (3H, s), 2.65-2.74 (2H, m),2.80-3.10 (2H, m), 3.95-4.32 (4H, m), 6.42 (1H, d, J = 7.6 Hz), 6.56(1H, d, J = 8.8 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.67 (1H, s), 8.00 (1H,t, J = 2.4 Hz), 8.19 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J =2.0 Hz), DMSO: 466 (M + H)⁺FAB 379 1.11-1.21 (2H, m), 1.27-1.49 (10H,m), 1.74-1.84 (4H, br), 2.83-2.92 (3H, br), 3.05 (1H, br), 3.71-3.75(2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.34 (1H, m), 7.58 (1H, m),7.66-7.71 (2H, m), 7.86 (1H, m), 8.00-8.03 (2H, m), 8.07 (1H, m), 8.19(1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 502 (M + H)⁺FAB 380 1.00-1.82(16H, m), 2.77-3.10 (4H, m), 3.95-4.23 (2H, m), 4.53 (2H, d, J = 12.0Hz), 7.15-7.26 (2H, m), 7.45-7.55 (2H, m), 7.62-7.70 (2H, m), 7.95-8.05(2H, m), 8.20 (1H, s), 8.46 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 1.7Hz), DMSO: 502 (M + H)⁺FAB 381 1.11-1.20 (2H, m), 1.27-1.32 (2H, m),1.47-1.61 (3H, m), 1.75-1.78 (2H, m), 2.34-2.44 (2H, m), 2.56-2.74 (4H,m), 2.88 (1H, t, J = 12.1 Hz), 3.04 (1H, t, J = 12.5 Hz), 3.23-3.41 (4H,m), 4.01 (1H, d, J = 13.0 Hz), 4.18 (1H, d, J = 12.4 Hz), 7.37 (1H, d, J= 5.6 Hz), 7.57-7.61 (1H, m), 7.68-7.71 (2H, m), 7.87 (1H, d, J = 8.1Hz), 8.01 (1H, t, J = 2.2 Hz), 8.06-8.10 (2H, m), 8.18 (1H, br), 8.55(1H, d, J = 2.4 Hz), 8.88 (1H, d, J = 1.8 Hz), DMSO: 503 (M + H)⁺FAB 3821.15-1.19 (2H, m), 1.27-1.49 (10H, m), 1.74-1.85 (4H, m), 2.70 (2H, m),2.89 (1H, t, J = 12.4 Hz), 3.04 (1H, t, J = 12.1 Hz), 3.26-3.31 (2H, m),4.02 (1H, m), 4.18 (1H, d, J = 12.4 Hz), 7.09 (1H, d, J = 14.8 Hz), 7.40(1H, t, J = 7.8 Hz), 7.46-7.51 (2H, m), 7.55 (1H, d, J = 8.3 Hz),7.64-7.70 (1H, br), 7.85-7.87 (1H, m), 8.17 (1H, t, J = 2.2 Hz),8.07-8.09 (1H, m), 8.15-8.21 (1H, br), 8.55 (1H, d, J = 2.8 Hz), 8.89(1H, d, J = 1.7 Hz), DMSO: 501 (M + H)⁺FAB

TABLE 61 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 383 0.87 (3H, t, J =6.4 Hz), 1.20-1.46 (8H, m), 1.54-1.72 (2H, m), 1.70 (2H, q, J = 6.4 Hz),1.81-1.94 (2H, m), 2.54-2.64 (1H, m), 2.85-3.05 (1H, m), 3.05-3.25 (1H,m), 3.91 (2H, t, J = 6.4 Hz), 4.00-4.16 (1H, m), 4.15-4.31 (1H, m),6.56-6.63 (1H, m), 7.07-7.13 (1H, m), 7.17 (1H, dd, J = 8.0, 8.0 Hz),7.29-7.36 (1H, m), 7.45 (1H, dd, J = 7.8, 5.2 Hz), 7.59-7.67 (1H, m),8.40-8.46 (2H, m), 9.90 (1H, s), DMSO: 440 (M + H)⁺FAB 384 0.87 (3H, t,J = 6.4 Hz), 1.20-1.45 (8H, m), 1.55-1.77 (4H, m), 1.80-1.93 (2H, m),2.52-2.62 (1H, m), 2.88-3.04 (1H, m), 3.04-3.19 (1H, m), 3.90 (2H, t, J= 6.4 Hz), 4.00-4.14 (1H, m), 4.16-4.30 (1H, m), 6.85 (2H, d, J = 8.8Hz), 7.45 (1H, dd, J = 8.3, 4.9 Hz), 7.49 (2H, d, J = 9.2 Hz), 7.61-7.66(1H, m), 8.40-8.45 (2H, m), 9.78 (1H, s), DMSO: 440 (M + H)⁺FAB 385 369(M + H)⁺FAB 386 480 (M + H)⁺FAB 387 424 (M + H)⁺FAB 388 0.85 (3H, t, J =7.2 Hz), 1.20-1.32 (6H, m), 1.45-1.58 (2H, m), 1.56-1.78 (2H, m),1.81-1.94 (2H, m), 2.48-2.54 (2H, m), 2.55-2.66 (1H, m), 2.90-3.05 (1H,m), 3.07-3.21 (1H, m), 4.00-4.15 (1H, m), 4.17-4.32 (1H, m), 7.10 (2H,d, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.68 (1H, br s), 8.04 (1H, dd,J = 2.8, 2.0 Hz), 8.19 (1H, br), 8.58 (1H, d, J = 2.8 Hz), 8.90 (1H, d,J = 2.0 Hz), 9.86 (1H, br), DMSO: 453 (M + H)⁺FAB 389 1.56-1.74 (2H,br), 1.88-2.04 (2H, br), 2.48-2.53 (3H, m), 3.25-3.55 (2H, br),3.65-3.92 (2H, br), 4.46-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.01(1H, s), 7.15 (1H, dt, J = 2.9, 8.8 Hz), 7.23-7.30 (2H, m), 7.40-7.47(1H, m), 7.70-8.30 (2H, br), DMSO 390 1.55-1.74 (2H, br), 1.88-2.04 (2H,br), 3.25-3.55 (2H, br), 3.65-3.92 (2H, br), 4.46-4.54 (1H, m), 5.07(2H, s), 6.95 (4H, s), 7.01 (1H, s), 7.15 (1H, dt, J = 2.9, 8.8 Hz),7.23-7.30 (2H, m), 7.40-7.47 (2H, m), 7.86-7.94 (1H, br), 7.97-8.05 (1H,br), 10.19 (1H, s), DMSO: 439 (M + H)⁺FAB 391 1.58-1.77 (2H, br),1.91-2.06 (2H, br), 3.28-3.41 (1H, br), 3.45-3.57 (1H, br), 3.65-3.78(1H, br), 3.82-3.94 (1H, br), 4.48-4.57 (1H, m), 5.07 (2H, s), 6.95 (4H,s), 7.11-7.18 (1H, m), 7.23-7.30 (2H, m), 7.40-7.47 (1H, m), 8.29-8.32(1H, m), 8.78 (1H, d, J = 2.5 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 448(M + H)⁺FAB 392 0.78-0.93 (2H, m), 1.04-1.26 (6H, m), 1.35-1.45 (2H, m),1.54-1.74 (9H, m), 1.90-2.04 (2H, br), 3.28-3.55 (2H, m), 3.66-3.95 (4H,m), 4.46-4.54 (1H, m), 6.84 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8Hz), 7.45 (1H, dd, J = 4.8, 8.4 Hz), 7.60-7.66 (1H, m), 8.41-8.45 (2H,m), DMSO: 453 (M + H)⁺FAB 393 415 (M + H)⁺FAB 394 387 (M + H)⁺FAB 3951.06-1.20 (2H, m), 1.43-1.82 (10H, m), 1.86-2.05 (3H, m), 3.24-3.57 (2H,br), 3.68-3.94 (4H, m) 4.51-4.55 (1H, m), 6.85 (2H, d, J = 9.2 Hz), 6.93(2H, d, J = 9.2 Hz), 8.08 (1H, dd, J = 1.6, 2.4 Hz), 8.66 (1H, d, J =2.4 Hz), 8.92 (1H, d, J = 1.6 Hz), 13.38-13.84 (1H, br), DMSO: 455 (M +H)⁺FAB 396 1.21-1.42 (2H, m), 1.78-1.90 (2H, br), 1.93-2.06 (1H, m),2.85-2.99 (1H, br), 3.01-3.15 (1H, br), 3.81 (2H, d, J = 8.0 Hz),3.99-4.12 (1H, br), 4.15-4.27 (1H, br), 5.07 (2H, s), 6.88 (2H, d, J =9.2 Hz), 6.94 (2H, d, J = 9.2 Hz), 7.11-7.18 (1H, m), 7.23-7.29 (2H, m),7.39-7.47 (2H, m), 7.62 (1H, ddd, J = 1.2, 2.4, 8.0 Hz), 8.40-8.45 (1H,m), DMSO: 437 (M + H)⁺FAB 397 414 (M + H)⁺FAB 398 386 (M + H)⁺FAB 3991.10-1.33 (2H, m), 1.45-1.61 (3H, m), 1.75-1.87 (2H, br), 2.64 (2H, t, J= 7.6 Hz), 2.80-3.10 (2H, br), 3.95-4.24 (2H, br), 7.12-7.32 (5H, m),7.90 (2H, d, J = 8.4 Hz), 7.98-8.08 (3H, m), 8.43-8.49 (1H, m),8.80-8.86 (1H, m), 12.80-13.30 (1H, m),, DMSO: 431 (M + H)⁺FAB

TABLE 62 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 400 1.06-1.30 (2H,m), 1.56-1.80 (3H, m), 2.47-2.52 (2H, m), 2.76-2.91 (1H, br), 2.93-3.07(1H, br), 3.92-4.05 (1H, br), 4.08-4.21 (1H, br), 5.10 (2H, s), 6.94(2H, d, J = 8.0 Hz), 7.08-7.18 (3H, m), 7.24-7.31 (2H, m), 7.40-7.48(1H, m), 7.71 (1H, dd, J = 4.8, 8.4 Hz), 7.93-7.99 (1H, m), 8.58 (1H, d,J = 4.4 Hz), 8.62-8.78 (1H, m), DMSO: 421 (M + H)⁺FAB 401 1.08-1.31 (2H,m), 1.58-1.79 (3H, m), 2.47-2.52 (2H, m), 2.76-3.05 (2H, br), 3.92-4.22(2H, br), 5.10 (2H, s), 6.94 (2H, d, J = 8.4 Hz), 7.08-7.19 (3H, m),7.24-7.31 (2H, m), 7.40-7.48 (1H, m), 7.98-8.03 (1H, m), 8.56-8.62 (1H,m), 8.87-8.93 (1H, br), DMSO: 465 (M + H)⁺FAB 402 1.07-1.28 (2H, br),1.43-1.60 (3H, m), 1.73-1.82 (2H, br), 2.62 (2H, t, J = 7.8 Hz),2.77-3.05 (2H, br), 3.92-4.20 (2H, br), 7.00 (1H, dd, J = 2.0, 2.4 Hz),7.14-7.31 (5H, m), 8.04 (1H, dd, J = 2.0, 2.4 Hz), 7.86-7.94 (1H, br),7.97-8.03 (1H, br), 10.06-10.26 (1H, br), DMSO: 327 (M + H)⁺FAB 403 351(M + H)⁺FAB 404 395 (M + H)⁺FAB 405 503 (M + H)⁺FAB 406 453 (M + H)⁺FAB407 1.02-1.51 (6H, m), 1.68-1.80 (4H, m), 2.28 (3H, s), 2.66-2.74 (2H,m), 2.82-3.09 (2H, m), 3.95-4.31 (4H, m), 6.43 (1H, d, J = 7.1 Hz), 6.56(1H, d, J = 8.5 Hz), 7.34-7.39 (1H, m), 7.65-7.69 (1H, br), 7.99-8.01(1H, m), 8.16-8.19 (1H, br), 8.55 (1H, d, J = 2.5 Hz), 8.88 (1H, d, J =1.9 Hz), DMSO: 452 (M + H)⁺FAB 408 502 (M + H)⁺FAB 409 369 (M + H)⁺FAB410 327 (M + H)⁺FAB 411 441 (M + H)⁺ESI 412 1.25-1.65 (6H, m), 2.25-2.48(6H, m), 2.57 (2H, t, J = 7.8 Hz), 3.36-3.64 (4H, m), 7.12-7.30 (5H, m),7.68 (1H, s), 8.03 (1H, t, J = 2.4 Hz), 8.19 (1H, s), 8.56 (1H, d, J =2.4 Hz), 8.90 (1H, d, J = 1.5 Hz), DMSO: 397 (M + H)⁺FAB 413 3.00-3.75(6H, m), 4.01-4.38 (4H, m), 5.17 (2H, s), 7.10 (2H, d, J = 8.8 Hz),7.13-7.21 (1H, m), 7.27-7.33 (2H, m), 7.42-7.49 (1H, m), 7.59 (2H, d, J= 8.8 Hz), 7.75 (1H, dd, J = 5.2, 7.6 Hz), 7.97-8.02 (1H, m), 8.62 (1H,d, J = 4.4 Hz), 8.70 (1H, d, J = 2.4 Hz), DMSO: 422 (M + H)⁺FAB 414 432(M + H)⁺FAB 415 431 (M + H)⁺FAB 416 299 (M + H)⁺FAB 417 1.33 (3H, t, J =6.8 Hz), 1.60-1.76 (2H, br), 1.91-2.07 (2H, br), 3.30-3.43 (1H, br),3.46-3.60 (1H, br), 3.67-3.75 (1H, br), 3.83-3.96 (1H, br), 4.35 (2H, q,J = 6.8 Hz), 4.47-4.57 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.11-7.19(1H, m), 7.23-7.30 (2H, m), 7.40-7.47 (1H, m), 7.84 (1H, dd, J = 2.4,8.8 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.58 (1H, d, J = 2.4 Hz), DMSO: 495(M + H)⁺FAB 418 1.58-1.77 (2H, br), 1.90-2.08 (2H, br), 3.28-3.60 (2H,br), 3.66-3.98 (2H, br), 4.47-4.54 (1H, m), 5.07 (2H, s), 6.96 (4H, s),7.10-7.19 (1H, m), 7.21-7.32 (2H, m), 7.38-7.49 (1H, m), 7.69-7.77 (1H,m), 8.04 (1H, d, J = 8.6 Hz), 8.60-8.70 (1H, m), DMSO: 467 (M + H)⁺FAB419 327 (M + H)⁺FAB 420 354 (M + H)⁺FAB 421 437 (M + H)⁺FAB 422 437 (M +H)⁺FAB 423 368 (M + H)⁺FAB

TABLE 63 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 424 369 (M + H)⁺ESI425 370 (M + H)⁺FAB 426 383 (M + H)⁺ESI 427 412 (M + H)⁺FAB 428 483 (M +H)⁺FAB 429 384 (M + H)⁺FAB 430 483 (M + H)⁺ESI 431 493 (M + H)⁺ESI 432522 (M + H)⁺ESI 433 466 (M + H)⁺FAB 434 480 (M + H)⁺ESI 435 438 (M +H)⁺ESI 436 427 (M + H)⁺ESI 437 481 (M + H)⁺FAB

TABLE 64 cell Ex FAAH IC₅₀ No. (nM) 002 0.11 003 0.073 009 0.67 010 0.10013 0.27 014 0.20 015 0.033 017 0.18 018 0.35 019 0.072 021 0.23 0230.040 030 0.19 033 0.077 034 0.046 036 0.044 037 0.69 038 0.028 039 0.30042 0.43 043 0.21 044 0.095 046 0.41 047 0.13 049 0.10 051 0.26 0530.063 055 0.44 061 0.35 063 0.12 065 0.41 066 0.057 069 0.095 070 0.099077 0.071 078 0.081 080 0.044 081 0.012 088 0.37 085 0.44 098 0.26 0990.099 100 0.035 101 0.078 103 0.092 104 0.066 108 0.052 113 0.056 1150.052 116 0.078 122 0.15 124 0.35 126 0.58 138 0.078 144 0.093 147 0.28149 0.45 151 0.17 152 0.18 154 0.17 155 0.061 159 0.23 160 0.51 173 0.69174 0.60 175 0.37 176 0.84 179 0.060 197 0.11 199 0.58 200 0.30 206 0.17207 0.31 208 0.13 218 0.44 225 0.89 228 0.22 261 0.54 263 0.036 266 0.31268 0.15 269 0.081 270 0.17 272 0.48 274 0.37 281 0.082 283 0.43 2840.36 285 0.47 287 0.031 289 0.16 292 0.65 293 0.24 294 0.60 300 0.43 3010.40 302 0.17 303 0.12 304 0.24 313 0.89 315 0.51 318 0.062 319 0.24 3200.081 321 0.040 322 0.058 323 0.085 324 0.50 325 0.54 326 0.13 327 0.12328 0.42 329 0.39 330 0.53 333 0.43 334 0.048 335 0.075 338 0.034 3390.12 340 0.052 341 0.078 342 0.33 344 0.13 345 0.18 346 0.27 349 0.054351 0.13 359 0.52 362 0.42 364 0.14 371 0.21 372 0.49 373 0.49 376 0.21378 0.20 380 0.35

TABLE 65

Com No R¹ R⁴ 1 HO₂C(CH₂)₃ H 2 Mo4□CH₂□₂NHCO(CH₂)₃ H 3 4-HexOPh□CH₂□₂NHCOCO₂H 4 4-OctPhNHCO CO₂H 5 Ph□CH₂□₂CONH CO₂Me 6 Ph□CH₂□₂CONH H 7Ph□CH₂□₂CONH CO₂H 8 Ph□CH₂□₄NHCO CO₂H 9 4-BuPhNHCO CO₂H 10 4-HexPhNHCOCO₂H 11 Py2(CH₂)₂NHCO H 12 Py3(CH₂)₂NHCO H 13 Ph(CH₂)₄NHCO CONH₂ 144-BuPhNHCO CONH₂ 15 Ph(CH₂)₃O(CH₂)₂ CO₂H 16 2-H₂NCOPhO(CH₂)₃ CO₂H 174-(3-FPhCH₂O)PhO

18 Ph(CH₂)₂

19 1-MeBenzIM□(CH₂)₃ CO₂H 20 Ph(CH₂)₂ CO₂Me 21 3-PIPE1Ph(CH₂)₂ CO₂H 22

CO₂H 23 Mo4CH₂ H 24 Mo4(CH₂)₂ CO₂Me 25 4-(3-FPhCH₂)PIPERA1(CH₂)₂ CO₂Me26 Mo4(CH₂)₃ CO₂Me 27 4-(3-FPhCH₂PIPERA1(CH₂)₂ H 28 Mo(CH₂)₃ H 29cPen(CH₂)₂ H 30 cPen(CH₂)₂ CO₂Me 31 cPen(CH₂)₂ CO₂H 32 cPen(CH₂)₂ CONH₂33 cHexCH₂ H 34 cHexCH₂ CO₂Me 35 cHexCH₂ CO₂H 36 cHexCH₂ CONH₂ 37cHex(CH₂)₃ H 38 cHex(CH₂)₃ CO₂Me 39 cHex(CH₂)₃ CO₂H 40 cHex(CH₂)₃ CONH₂41 Ph(CH₂)₃ H 42 Ph(CH₂)₃ CONH₂ 43 3-FPh(CH₂)₃ H 44 3-FPh(CH₂)₃ CO₂Me 453-FPh(CH₂)₃ CO₂H 46 3-FPh(CH₂)₃ CONH₂ 47 3-ClPh(CH₂)₃ H 48 3-ClPh(CH₂)₃CO₂Me 49 3-ClPh(CH₂)₃ CO₂H 50 3-ClPh(CH₂)₃ CONH₂ 51 3-NCPh(CH₂)₃ H 523-NCPh(CH₂)₃ CO₂Me 53 3-NCPh(CH₂)₃ CO₂H 54 3-NCPh(CH₂)₃ CONH₂ 553-MeOPh(CH₂)₃ H 56 3-MeOPh(CH₂)₃ CO₂Me 57 3-MeOPh(CH₂)₃ CO₂H 583-MeOPh(CH₂)₃ CONH₂ 59 4-FPh(CH₂)₃ H 60 4-PPh(CH₂)₃ CO₂Me 61 4-FPh(CH₂)₃CO₂H 62 4-FPh(CH₂)₃ CONH₂

TABLE 66

Com No R¹ R⁴ 63 4-ClPh(CH₂)₃ H 64 4-ClPh(CH₂)₃ CO₂Me 65 4-ClPh(CH₂)₃CO₂H 66 4-ClPh(CH₂)₃ CONH₂ 67 4-NCPh(CH₂)₃ H 68 4-NCPh(CH₂)₃ CO₂Me 694-NCPh(CH₂)₃ CO₂H 70 4-NCPh(CH₂)₃ CONH₂ 71 4-MeOPh(CH₂)₃ H 724-MeOPh(CH₂)₃ CO₂Me 73 4-MeOPh(CH₂)₃ CO₂H 74 4-MeOPh(CH₂)₃ CONH₂ 752-FPh(CH₂)₃ H 76 2-FPh(CH₂)₃ CO₂Me 77 2-FPh(CH₂)₃ CO₂H 78 2-FPh(CH₂)₃CONH₂ 79 2-ClPh(CH₂)₃ H 80 2-ClPh(CH₂)₃ CO₂Me 81 2-ClPh(CH₂)₃ CO₂H 822-ClPh(CH₂)₃ CONH₂ 83 2-NCPh(CH₂)₃ H 84 2-NCPh(CH₂)₃ CO₂Me 852-NCPh(CH₂)₃ CO₂H 86 2-NCPh(CH₂)₃ CONH₂ 87 2-MeOPh(CH₂)₃ H 882-MeOPh(CH₂)₃ CO₂Me 89 2-MeOPh(CH₂)₃ CO₂H 90 2-MeOPh(CH₂)₃ CONH₂ 913,4-diFPh(CH₂)₃ H 92 3,4-diFPh(CH₂)₃ CO₂Me 93 3,4-diFPh(CH₂)₃ CO₂H 943,4-diFPh(CH₂)₃ CONH₂ 95 3,5-diFPh(CH₂)₃ H 96 3,5-diFPh(CH₂)₃ CO₂Me 973,5-diFPh(CH₂)₃ CO₂H 98 3,5-diFPh(CH₂)₃ CONH₂ 99 2,5-diFPh(CH₂)₃ H 1002,5-diFPh(CH₂)₃ CO₂Me 101 2,5-diFPh(CH₂)₃ CO₂H 102 2,5-diFPh(CH₂)₃ CONH₂103 3-NC-5-FPh(CH₂)₃ H 104 3-NC-5-FPh(CH₂)₃ CO₂Me 105 3-NC-5-FPh(CH₂)₃CO₂H 106 3-NC-5-FPh(CH₂)₃ CONH₂ 107 3-FPh(CH₂)₂ H 108 3-CIPh(CH₂)₂ H 1093-NCPh(CH₂)₂ H 110 3-MeOPh(CH₂)₂ H 111 3-H₂NCOPh(CH₂)₂ H 1123-Me₂NCOPh(CH₂)₂ H 113 3-PIPE1COPh(CH₂)₂ H 114 3-PYRR1COPh(CH₂)₂ H 1153-EtNHCOPh(CH₂)₂ H 116 3-Et₂NCOPh(CH₂)₂ H 117 3-cHexNHCOPh(CH₂)₂ H 1184-FPh(CH₂)₂ H 119 4-ClPh(CH₂)₂ H 120 4-NCPh(CH₂)₂ H 121 4-MeOPh(CH₂)₂ H122 4-Me₂NCOPh(CH₂)₂ H 123 4-PIPE1COPh(CH₂)₂ H 124 4-PYRR1COPh(CH₂)₂ H125 4-EtNHCOPh(CH₂)₂ H 126 4-Et₂NCOPh(CH₂)₂ H

TABLE 67

Com No R¹ R⁴ 127 4-cHexNHCOPh(CH₂)₂ H 128 2-FPh(CH₂)₂ H 129 2-ClPh(CH₂)₂H 130 2-NCPh(CH₂)₂ H 131 2-MeOPh(CH₂)₂ H 132 3,4-diFPh(CH₂)₂ H 1333,4-diFPh(CH₂)₂ CO₂Me 134 3,4-diFPh(CH₂)₂ CO₂H 135 3,4-diFPh(CH₂)₂ CONH₂136 3,5-diFPh(CH₂)₂ H 137 3,5-diFPh(CH₂)₂ CO₂Me 138 3,5-diFPh(CH₂)₂ CO₂H139 3,5-diFPh(CH₂)₂ CONH₂ 140 2,5-diFPh(CH₂)₂ H 141 2,5-diFPh(CH₂)₂CO₂Me 142 2,5-diFPh(CH₂)₂ CO₂H 143 2,5-diFPh(CH₂)₂ CONH₂ 1443-Cl-4-FPh(CH₂)₂ H 145 3-Cl-4-FPh(CH₂)₂ CO₂Me 146 3-Cl-4-FPh(CH₂)₂ CO₂H147 3-Cl-4-FPh(CH₂)₂ CONH₂ 148 3-Cl-5-FPh(CH₂)₂ H 149 3-Cl-5-FPh(CH₂)₂CO₂Me 150 3-Cl-5-FPh(CH₂)₂ CO₂H 151 3-Cl-5-FPh(CH₂)₂ CONH₂ 1522-F-5-ClPh(CH₂)₂ H 153 2-F-5-ClPh(CH₂)₂ CO₂Me 154 2-F-5-ClPh(CH₂)₂ CO₂H155 2-F-5-ClPh(CH₂)₂ CONH₂ 156 3-MeO-4-FPh(CH₂)₂ H 157 3-MeO-4-FPh(CH₂)₂CO₂Me 158 3-MeO-4-FPh(CH₂)₂ CO₂H 159 3-MeO-4-FPh(CH₂)₂ CONH₂ 1603-F-5-MeOPh(CH₂)₂ H 161 3-F-5-MeOPh(CH₂)₂ CO₂Me 162 3-F-5-MeOPh(CH₂)₂CO₂H 163 3-F-5-MeOPh(CH₂)₂ CONH₂ 164 2-F-5-MeOPh(CH₂)₂ H 1652-F-5-MeOPh(CH₂)₂ CO₂Me 166 2-F-5-MeOPh(CH₂)₂ CO₂H 167 2-F-5-MeOPh(CH₂)₂CONH₂ 168 2,4-diFPh(CH₂)₂ H 169 2,4-diFPh(CH₂)₂ CO₂Me 1702,4-diFPh(CH₂)₂ CO₂H 171 2,4-diFPh(CH₂)₂ CONH₂ 172 2-F-4-ClPh(CH₂)₂ H173 2-F-4-ClPh(CH₂)₂ CO₂Me 174 2-F-4-ClPh(CH₂)₂ CO₂H 1752-F-4-ClPh(CH₂)₂ CONH₂ 176 2-F-4-NCPh(CH₂)₂ H 177 2-F-4-NCPh(CH₂)₂ CO₂Me178 2-F-4-NCPh(CH₂)₂ CO₂H 179 2-F-4-NCPh(CH₂)₂ CONH₂ 1802-F-4-MeOPh(CH₂)₂ H 181 2-F-4-MeOPh(CH₂)₂ CO₂Me 182 2-F-4-MeOPh(CH₂)₂CO₂H 183 2-F-4-MeOPh(CH₂)₂ CONH₂ 184 BIP3(CH₂)₂ H 185 3′-FBIP3(CH₂)₂ H186 3′-NCBIPe(CH₂)₂ H 187 3′-MeOBIP3(CH₂)₂ H 188 3′,4′-diFBIP3(CH₂)₂ H189 3′-MeO-4′-FBIP3(CH₂)₂ H 190 BIP4(CH₂)₂ H 191 3′-FBIP4(CH₂)₂ H 1923′-NCBIP4(CH₂)₂ H

TABLE 68

Com No R¹ R⁴ 193 3′-MeOBIP4(CH₂)₂ H 194 3′,4′-diFBIP4(CH₂)₂ H 1953′-MeO-4′-FBIP4(CH₂)₂ H 196 3-Py2Ph(CH₂)₂ H 197 3-MeOPhNHCO H 1984-MeOPhNHCO H 199 3-MeO-4-FPhNHCO H 200 3-F-5-MeOPhNHCO H 2012-F-5-MeOPhNHCO H 202 3-F-4-MeOPhNHCO H 203 2-F-4-MeOPhNHCO H 2041-(6-MePy2)PIPE4(CH₂)₃ H 205 1-(6-MePy2)PIPE4CH₂ H 206 1-PhCOPIPE4(CH₂)₃H 207 1-(6-MePy2)PIPE4(CH₂)₂ H 208 1-(6-MePy2)PIPERA4(CH₂)₃ H 2091-QUI2PIPE4(CH₂)₃ H 210 1-ISOQUI1PIPE4(CH₂)₃ H 2111-ISOQUI1PIPERA4(CH₂)₃ H 212 1-NAPH1PIPE4(CH₂)₃ H 213

H 214

CONH₂

TABLE 69

Com No R¹ R⁴ 215 Ph(CH₂)₄ CO₂H 216 Ph CO₂H 217 Ph(CH₂)₃ CONH(CH₂)₂OH 218Ph(CH₂)₅ CO₂H 219 cHex(CH₂)₂ H 220 Ph(CH₂)₄ H 221 Ph(CH₂)₃ H 2223-MePh(CH₂)₂ H 223 3-MeOPh(CH₂)₂ H 224 3-FPh(CH₂)₂ H 225 3-NCPh(CH₂)₂ H226 4-MePh(CH₂)₂ H 227 4-MeOPh(CH₂)₂ H 228 4-FPh(CH₂)₂ H 2294-NCPh(CH₂)₂ H 230 2-MePh(CH₂)₂ H 231 2-MeOPh(CH₂)₂ H 232 2-FPh(CH₂)₂ H233 2-NCPh(CH₂)₂ H 234 3-Me-4-FPh(CH₂)₂ H 235 3-F-5-MePh(CH₂)₂ H 2362-F-5-MePh(CH₂)₂ H 237 3-MeO-4-FPh(CH₂)₂ H 238 3-F-5-MeOPh(CH₂)₂ H 2392-F-5-MeOPh(CH₂)₂ H 240 3,4-diFPh(CH₂)₂ H 241 3,5-diFPh(CH₂)₂ H 2422,5-diFPh(CH₂)₂ H 243 3-iPrOPh(CH₂)₂ H 244 3-NC-4-FPh(CH₂)₂ H 2454-tBucHex(CH₂)₂ H 246 3-H₂NCOPh(CH₂)₂ H 247 1-(6-MePy2)PIPE4(CH₂)₃ H 2483-cHexCH₂OPhCO CONH₂ 249 3-cHex(CH₂)₂OPhCO CONH₂ 250 3-cHepCH₂OPhCOCONH₂ 251 3-PhCH₂OPhCO CONH₂ 252 4-PhCH₂OPhCO CONH₂ 253 3-cOctCH₂OPhCOCONH₂ 254 4-cHexCH₂N(Me)PhCO CONH₂ 255 4-(3-ClPhCH₂O)PhCO CONH₂ 2564-(3-F₃CPhCH₂O)PhCO CONH₂ 257 4-(3-MeOPhCH₂O)PhCO CONH₂ 2584-(3-NCPhCH₂O)PhCO CONH₂ 259 4-(3,5-diFPhCH₂O)PhCO CONH₂ 2604-cHexCH₂OPhCO CONH₂ 261 PhCH₂OCO CONH₂ 262 4-tBuOPhCO CONH₂ 2634-PhCH₂OPhCH₂ CONH₂ 264 4-H₂NCOPhOCH₂CO CONH₂ 265 Ph(CH₂)₂OCO CONH₂ 2663-MePh(CH₂)₂ CONH₂ 267 3-MeOPh(CH₂)₂ CONH₂ 268 3-FPh(CH₂)₂ CONH₂ 2693-NCPh(CH₂)₂ CONH₂ 270 4-MePh(CH₂)₂ CONH₂ 271 4-MeOPh(CH₂)₂ CONH₂ 2724-FPh(CH₂)₂ CONH₂ 273 4-NCPh(CH₂)₂ CONH₂ 274 2-MePh(CH₂)₂ CONH₂ 2752-MeOPh(CH₂)₂ CONH₂ 276 2-FPh(CH₂)₂ CONH₂ 277 2-NCPh(CH₂)₂ CONH₂ 2783-MeO-4-FPh(CH₂)₂ CONH₂ 279 2-F-3-MeOPh(CH₂)₂ CONH₂ 2802-F-5-MeOPh(CH₂)₂ CONH₂ 281 3-Me-4-FPh(CH₂)₂ CONH₂ 282 3-F-5-MePh(CH₂)₂CONH₂

TABLE 70

Com No R¹ R⁴ 283 2-F-5-MePh(CH₂)₂ CONH₂ 284 3,4-diFPh(CH₂)₂ CONH₂ 2853,5-diFPh(CH₂)₂ CONH₂ 286 2,5-diFPh(CH₂)₂ CONH₂ 287 4-tBucHex(CH₂)₂CONH₂ 288 3-cHexCH₂OPhCO CO₂Me 289 3-cHex(CH₂)₂OPhCO CO₂Me 2903-cHepCH₂OPhCO CO₂Me 291 3-PhCH₂OPhCO CO₂Me 292 4-PhCH₂OPhCO CO₂Me 2933-cOctCH₂OPhCO CO₂Me 294 4-[3-FPhCH₂N(Me)]PhCO CO₂Me 2954-[3,4-diFPhCH₂N(Me)]PhCO CO₂Me 296 4-[3,5-diFPhCH₂N(Me)]PhCO CO₂Me 2974-[2,5-diFPhCH₂N(Me)]PhCO CO₂Me 298 4-cHexCH₂N(Me)PhCO CO₂Me 2994-(3-ClPhCH₂O)PhCO CO₂Me 300 4-(3-F₃CPhCH₂O)PhCO CO₂Me 3014-(3-MeOPhCH₂O)PhCO CO₂Me 302 4-(3-MeO-4-FPhCH₂O)PhCO CO₂Me 3034-(3-F-5-MeOPhCH₂O)PhCO CO₂Me 304 4-(3-NCPhCH₂O)PhCO CO₂Me 3054-(3,5-diFPhCH₂O)PhCO CO₂Me 306 4-cHexCH₂OPhCO CO₂Me 307 PhCH₂OCO CO₂Me308 4-tBuOPhCO CO₂Me 309 4-PhCH₂OPhCH₂ CO₂Me 310 4-H₂NCOPhOCH₂CO CO₂Me311 Ph(CH₂)₂OCO CO₂Me 312 3-Cl-4-(3-NCPhCH₂O)PhCO CO₂Me 3132-Cl-4-(3-NCPhCH₂O)PhCO CO₂Me 314 4-[3-FPhCH₂N(Me)]PhCO CO₂H 3154-cHexCH₂N(Me)PhCO CO₂H 316 4-(3-ClPhCH₂O)PhCO CO₂H 317 3-MePh(CH₂)₂CO₂Me 318 3-MeOPh(CH₂)₂ CO₂Me 319 3-FPh(CH₂)₂ CO₂Me 320 3-NCPh(CH₂)₂CO₂Me 321 4-MePh(CH₂)₂ CO₂Me 322 4-MeOPh(CH₂)₂ CO₂Me 323 4-FPh(CH₂)₂CO₂Me 324 4-NCPh(CH₂)₂ CO₂Me 325 2-MePh(CH₂)₂ CO₂Me 326 2-MeOPh(CH₂)₂CO₂Me 327 2-FPh(CH₂)₂ CO₂Me 328 2-NCPh(CH₂)₂ CO₂Me 329 3-Me-4-FPh(CH₂)₂CO₂Me 330 2-F-5-MePh(CH₂)₂ CO₂Me 331 3-F-5-MePh(CH₂)₂ CO₂Me 3323-MeO-4-FPh(CH₂)₂ CO₂Me 333 2-F-5-MeOPh(CH₂)₂ CO₂Me 3343-F-5-MeOPh(CH₂)₂ CO₂Me 335 3,4-diFPh(CH₂)₂ CO₂Me 336 2,5-diFPh(CH₂)₂CO₂Me 337 3,5-diFPh(CH₂)₂ CO₂Me 338 4-tBucHex(CH₂)₂ CO₂Me 3393-cHexCH₂OPhCO CO₂H 340 3-cHex(CH₂)₂OPhCO CO₂H 341 3-cHepCH₂OPhCO CO₂H342 3-PhCH₂OPhCO CO₂H 343 4-PhCH₂OPhCO CO₂H 344 3-cOctCH₂OPhCO CO₂H 3454-(3-F₃CPhCH₂O)PhCO CO₂H 346 4-(3-MeOPhCH₂O)PhCO CO₂H 3474-(3-NCPhCH₂O)PhCO CO₂H 348 4-(3,5-diFPhCH₂O)PhCO CO₂H 3494-cHexCH₂OPhCO CO₂H 350 PhCH₂OCO CO₂H

TABLE 71

Com No R¹ R⁴ 351 4-tBuOPhCO CO₂H 352 4-PhCH₂OPhCH₂ CO₂H 3534-H₂NCOPhOCH₂CO CO₂H 354 Ph(CH₂)₂OCO CO₂H 355 3-Cl-4-(3-NCPhCH₂O)PhCOCO₂H 356 2-Cl-4-(3-NCPhCH₂O)PhCO CO₂H 357 3-MePh(CH₂)₂ CO₂H 3583-MeOPh(CH₂)₂ CO₂H 359 3-FPh(CH₂)₂ CO₂H 360 3-NCPh(CH₂)₂ CO₂H 3614-tBucHex(CH₂)₂ CO₂H 362 4-(4-FPhCH₂O)PhCO CONH₂ 363 4-(4-FPhCH₂O)PhCOCO₂Me 364 4-(4-FPhCH₂O)PhCO CO₂H 365 4-(3,4-diFPhCH₂O)PhCO CONH₂ 3664-(3,4-diFPhCH₂O)PhCO CO₂Me 367 4-(2,4-diFPhCH₂O)PhCO CONH₂ 3684-(2,4-diFPhCH₂O)PhCO CO₂Me 369 Ph(CH₂)₂ CONH₂ 370 Ph(CH₂)₄ CONH₂ 3714-[3-FPhCH₂N(Me)]PhCO CONH₂ 372 4-[3,4-diFPhCH₂N(Me)]PhCO CONH₂ 3734-[3,5-diFPhCH₂N(Me)]PhCO CONH₂ 374 4-[3-MeO-4-FPhCH₂N(Me)]PhCO CONH₂375 4-[3-F-5-MeOPhCH₂N(Me)]PhCO CONH₂ 376 3-Cl-4-(3-NCPhCH₂O)PhCO CONH₂377 2-Cl-4-(3-NCPhCH₂O)PhCO CONH₂

TABLE 72 Com No Str 378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

TABLE 73 Com No Str 400

401

402

403

404

405

406

INDUSTRIAL APPLICABILITY

The compounds of the present invention have an excellent FAAH-inhibitoryactivity, and are useful for treatment of FAAH-associated disorders,especially urinary frequency and urinary incontinence, overactivebladder and/or pain.

SEQUENCE LISTING FREE TEXT

The inventor is shown in the numeral entry <223> of SEQ ID NO:1 in thefollowing sequence listing.

1. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylatecompound of a general formula (I) or its pharmaceutically acceptablesalt:

wherein the symbols in formula (I) have the following meanings: HET¹represents a 5- to 7-membered non-aromatic nitrogen-containing heteroring, R¹, R² and R³ are the same or different, each representing (1) H;(2) OH; (3) HO—CO—, lower alkyl-O—CO—, aryl-lower alkyl-O—CO—, orH₂N—CO-aryl-lower alkyl-O—CO—; (4) cyano; (5) lower alkyl-CO—; (6) oxo(═O); (7) a formula [R¹⁰¹—(O)m1]m2-[ALK¹ optionally substituted withOH]—(O)n1-, wherein m1 and n1 are the same or different, each indicating0 or 1; m2 is from 1 to 5; ALK¹ represents lower alkylene, loweralkenylene or lower alkynylene; R¹⁰¹ represents (i) H; (ii) aryl groupAr_(1a) optionally substituted with at least one substituent selectedfrom the group consisting of: (a) H₂N—, (b) halo, (c) cyano, (d)optionally-esterified carboxyl, (e) a group R^(1011a)R^(1012a)N—CO—, (f)nitrogen-containing hetero ring HET², (g) Ar^(1a) optionally substitutedwith halo, cyano, OH, lower alkyl-O— or lower alkyl, (h) lower alkyl,(j) OH, (k) lower alkyl-O— optionally substituted with Ar^(1a) orhalo-Ar^(1a), (l) HET²-CO— optionally substituted with halo, Ar^(1a) orHETAr^(1a),  wherein HETAr^(1a) represents nitrogen-containingheteroaryl, (s) HET²-CONR^(1011a)—, (t) H₂NCONH—, and (u)optionally-esterified carboxyl-ALK^(2a), wherein ALK^(2a) representslower alkyl or lower alkenyl; (iii) ALK^(2a) optionally substituted witha group R^(1011a)R^(1012a)N or Ar^(1a), wherein R^(1011a) and R^(1012a)are the same or different, each representing  (a) H;  (b) cycloalkylgroup cALK;  (c) ALK^(2a) optionally substituted with halo, cALK, OH,lower alkyl-O— or Ar^(1a); or  (d) Ar^(1a)—SO₂— optionally substitutedwith halo; (iv) HET² optionally substituted with at least onesubstituent selected from the group consisting of (a) ALK^(2a)optionally substituted with Ar^(1a) or halo-Ar^(1a), (b) Ar^(1a), (c)HETAr^(1a) optionally substituted with lower alkyl, and (d) Ar^(1a)—CO—or halo-Ar^(1a)—CO—; (v) cALK optionally substituted with ALK^(2a), or(vi) optionally-esterified carboxyl, wherein when m2 is from 2 to 5,then [R¹⁰¹—(O)m1]'s may be the same or different; (8) a groupR¹⁰²-ALK¹—N(R¹⁰³)—CO—, wherein R¹⁰² represents (i) H; (ii) cALK; (iii)HETAR^(1a); or (iv) Ar^(1a) optionally substituted with at least onesubstituent selected from the group consisting of (a) HO, (b)ALK^(2a)—O—, (c) cALK-ALK¹—O—, (d) cALK—Ar^(1a)-ALK¹—O—, and (e)Ar^(1a)-ALK¹—O—; R¹⁰³ represents (i) H; (ii) cALK; (iii) ALK^(2a)optionally substituted with at least one substituent selected from thegroup consisting of (a) HET², (b) Ar^(1a), and (c) halo-Ar^(1a); (iv)HETAR^(a); or (v) Ar^(1a)—[CO]m1 optionally substituted with at leastone substituent selected from the group consisting of (a) cALK, (b) H₂N,(c) a group R^(1011a)R^(1012a)N—CO—, and (d) ALK^(2a)); (9) a groupR^(104a)R^(105a)N—[CO]m1-ALK¹—, wherein R^(104a) and R^(105a) are thesame or different, each representing a group R¹⁰³; (10) a groupR¹⁰⁶-ALK³-L¹-, wherein R¹⁰⁶ represents (i) a group R^(10l)—(O)m1-; (ii)a group R^(104a)R^(105a)N—; (iii) a group ALK^(2a)—CONH—; or (iv) agroup Ar^(1a)—CONH—; ALK³ represents lower alkylene, lower alkenylene orcycloalkylene, L¹ represents —C(═O)— or —SO₂—; (11) ALK^(2a)—CONH—optionally substituted with Ar^(1a); (12) Ar^(1a) substituted with halo;(13) a group [R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-, wherein Ar² represents arylene,and R¹⁰⁷ represents (i) H; (ii) halo; (iii) ALK^(2a) optionallysubstituted with at least one substituent selected from the groupconsisting of (a) HO, (b) cALK, (c) HET², (d) Ar^(1a) optionallysubstituted with halo, lower alkyl, lower alkyl-O—, a groupR^(1011a)R^(1012a)N—[CO]p-, cyano or optionally-esterified carboxyl, (e)optionally-esterified carboxyl, (f) HET²-[CO]p- optionally substitutedwith a group R^(1011a)R^(1012a)N—[CO]p-, and (g) a groupR^(1011a)R^(1012a)N—[CO]p-, wherein p indicates 0 or 1, (iv) a groupR^(1011a)R^(1012a)N—[CO]p-; or (v) a groupR^(1011a)R^(1012a)N—[CO]p-Ar^(1a), wherein when m2 is from 2 to 5, then[R¹⁰⁷—(O)m1]'s may be the same or different, and further the group[R¹⁰⁷—(O)m1]m2 may be methylenedioxy to form a ring; (14) a group[R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—, wherein when m2 is from 2 to 5, then[R¹⁰⁷—(O)m1]'s may be the same or different; (15) a group[R^(1011a)R^(1012a)N—[CO]m1]m2-Ar²—(O)m1-, wherein when m2 is from 2 to5, then [R^(1011a)R^(1012a)N—[CO]m1]'s may be the same or different;(16) a group [R¹⁰⁸]m2-Ar²-L²-, wherein R¹⁰⁸ represents (i) H; (ii) halo;(iii) HO; (iv) cALK—O—; (v) a group R¹⁰⁹-ALK¹—(O)m1- (R¹⁰⁹ represents (a) H;  (b) cALK;  (c) Ar^(1a) optionally substituted with at least onesubstituent selected from the group consisting of  (1′) halo,  (2′)cyano,  (3′) NO₂,  (4′) ALK^(2a) optionally substituted with halo,  (5′)HO,  (6′) ALK^(2a)—O— optionally substituted with halo,  (7′)optionally-esterified carboxyl, and  (8′) a group R^(104a)R^(105a)N—, (d) HETAr^(1a), or  (e) a group R^(104a)R^(105a)N—[CO]m1-), (vi) agroup R¹⁰¹³R¹⁰¹⁴N—, wherein R¹⁰¹³ and R¹⁰¹⁴ are the same or different,each representing  (i) H;  (ii) ALK^(2a);  (iii) cALK-ALK¹—; or  (iv)Ar^(1a)-ALK¹— optionally substituted with at least one substituentselected from the group consisting of  (1′) halo,  (2′) cyano,  (3′)ALK^(2a) optionally substituted with halo, and  (4′) ALK^(2a)—O—optionally substituted with halo; or (vii) HET²-(O)m1- optionallysubstituted with lower alkyl, wherein L² represents —CO— or —S(O)_(q)—,q indicates 0, 1 or 2, and when m2 is from 2 to 5, then [R¹⁰⁸]'s may bethe same or different; (17) a group [R¹⁰¹]m2-Ar²—CONH—, wherein when m2is from 2 to 5, then [R¹⁰¹]'s may be the same or different; (18) a group[R¹¹¹]m2-HETAr²—(O)m1-, wherein R¹¹¹ represents (i) H; (ii) halo; (iii)oxo (═O); or (iv) a group R^(103a)—(O)n1-, R^(103a) represents  (i) H; (ii) cALK;  (iii) ALK^(2a) optionally substituted with at least onesubstituent selected from the group consisting of  (a) HET²,  (b)Ar^(1a),  (c) cALK, and  (d) halo-Ar^(1a);  (iv) HETAr^(1a); or  (v)Ar^(1a) optionally substituted with at least one substituent selectedfrom the group consisting of (a) cALK, (b) H₂N, and (c) a groupR^(1011a)R^(1012a)N—CO—, wherein HETAr² represents nitrogen-containingheteroarylene, and  when m2 is from 2 to 5, then [R¹¹¹]'s may be thesame or different; (19) a formula [R¹¹²]m2-HETAr²—N(R¹⁰³)—CO—, whereinR¹¹² represents (i) H; (ii) cALK; (iii) ALK^(2a); or (iv) Ar^(1a)optionally substituted with at least one substituent selected from thegroup consisting of (a) halo, (b) HO, (c) ALK^(2a)—O—, and (d)Ar^(1a)-ALK¹—O—, wherein when m2 is from 2 to 5, then [R¹¹²]'s may bethe same or different; or (20) a formula [R¹⁰⁸]m2-HETAr²-L²-, whereinwhen m2 is from 2 to 5, then [R¹⁰⁸]'s may be the same or different,provided that, when any one group of R¹, R² and R³ is a group[R¹¹¹]m2-HETAr²—(O)m1- and when m1 is 0, then the remaining groups ofR¹, R² and R³ are H; R⁴, R⁵, R⁶ and R⁷ are H, provided that pyridin-3-yl4-methylpiperazine-1-carboxylate and pyridin-2-yl2-oxopyridin-1(2H)-carboxylate are excluded.
 2. The pyridyl non-aromaticnitrogen-containing heterocyclic-1-carboxylate compound or itspharmaceutically acceptable salt according to claim 1, represented by ageneral formula (II):

wherein T represents CH₂, NH, NHCH₂ or O, and each of the H's in T isoptionally substituted with R¹, R², or R³.
 3. The pyridyl non-aromaticnitrogen-containing heterocyclic-1-carboxylate compound or itspharmaceutically acceptable salt according to claim 2, wherein R¹, R²and R³ are the same or different, each representing H, a group[R^(10l)—(O)m1]m2-[ALK¹ optionally substituted with OH]—(O)n1-, a groupR¹⁰²-ALK¹—N(R¹⁰³)—CO—, a group R¹⁰⁶-ALK³-L¹-, a group[R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-, a group [R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—, or agroup [R¹⁰⁸]m2-Ar²-L²-.
 4. A pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate compound of a general formula (III) or itspharmaceutically acceptable salt:

wherein the symbols in formula (III) have the following meanings: ring Arepresents benzene ring, cyclopentane ring, cyclohexane ring,cycloheptane ring, or 5- to 7-membered nitrogen-containing hetero ring;L represents single bond, lower alkylene, lower alkenylene,—N(R¹⁵)—C(═O)—, —C(═O)—N(R¹⁵)—, -(lower alkenylene)-C(═O)—, —O—, or—C(═O)—; R¹⁵ represents H, or lower alkyl; X represents CH, or N; R⁸,R⁹, and R¹⁰ are the same or different, each representing (i) a groupselected from the group consisting of H, halo, —CN, —CF₃, lower alkyl,and —O-lower alkyl; (ii) aryl optionally substituted with one or moregroups selected from the group consisting of H, halo, —CN, —CF₃, loweralkyl, and —O-lower alkyl; (iii) nitrogen-containing heteroaryloptionally substituted with one or more groups selected from the groupconsisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (iv)R¹⁶-(lower alkylene)-O—; (v) R¹⁶-(lower alkylene)-N(R¹⁵)—; or (vi)R¹⁷R¹⁸N—C(═O)—, wherein R¹⁶ represents (i) aryl optionally substitutedwith one or more groups selected from the group consisting of H, halo,—CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii) nitrogen-containingheteroaryl optionally substituted with one or more groups selected fromthe group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-loweralkyl; or (iii) 3- to 8-membered cycloalkyl, wherein R¹⁷ and R¹⁸ are thesame or different, each representing H, lower alkyl, or 3- to 8-memberedcycloalkyl, or R¹⁷ and R¹⁸ may form, together with the N atom bondingthereto, 3- to 8-membered nitrogen-containing hetero ring, R¹¹represents H, lower alkyl, or oxo (═O), and R¹², R¹³ and R¹⁴ are H. 5.The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylatecompound or its pharmaceutically acceptable salt according to claim 4,wherein the ring A is benzene ring, cyclohexane ring, piperidine ring,or piperazine ring.
 6. The pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate compound or its pharmaceutically acceptablesalt according to claim 5, wherein R⁹, R¹⁰, and R¹¹ are H.
 7. A pyridylnon-aromatic nitrogen-containing heterocyclic-1-carboxylate compound ofa general formula (IV) or its pharmaceutically acceptable salt:

wherein the symbols in formula (IV) have the following meanings: ring A¹represents benzene ring, piperidine ring or piperazine ring; L¹represents lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, or —O—,wherein R¹⁵ represents H, or lower alkyl; R¹⁹ represents (i) a groupselected from the group consisting of H, halo, —CN, —CF₃, lower alkyl,and —O-lower alkyl; (ii) nitrogen-containing heteroaryl optionallysubstituted with one or more groups selected from the group consistingof H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (iii) R¹⁶-(loweralkylene)-O—; or (iv) R¹⁷R¹⁸N—C(═O)—, wherein R¹⁶ represents (i) aryloptionally substituted with one or more groups selected from the groupconsisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii)nitrogen-containing heteroaryl optionally substituted with the groupconsisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; or(iii) 3- to 8-membered cycloalkyl, wherein R¹⁷ and R¹⁸ are the same ordifferent, each representing H or lower alkyl, or R¹⁷ and R¹⁸ may form,together with the N atom bonding thereto, 5- or 6-memberednitrogen-containing hetero ring, and R²⁰ represents H.
 8. A pyridylnon-aromatic nitrogen-containing heterocyclic-1-carboxylate compound ofa general formula (V) or its pharmaceutically acceptable salt:

wherein the symbols in formula (V) have the following meanings: L²represents lower alkylene, lower alkenylene, or -(loweralkenylene)-C(═O)—, R²¹ represents H, halo, —CN, —CF₃, lower alkyl, or—O-lower alkyl, and R²² represents H.
 9. The pyridyl non-aromaticnitrogen-containing heterocyclic-1-carboxylate compound or itspharmaceutically acceptable salt according to claim 1, the compoundbeing one among the following group: pyridin-3-yl4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate, pyridin-3-yl4-[(2E)-3-phenylprop-2-enoyl]piperazine-1-carboxylate, pyridin-3-yl4-(anilinocarbonyl)piperidine-1-carboxylate, and pyridin-3-yl4-(2-phenylethyl)piperazine-1-carboxylate.
 10. A pharmaceuticalcomposition comprising the pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate compound or its pharmaceutically acceptablesalt of claim 1 as an active ingredient thereof.
 11. The pharmaceuticalcomposition according to claim 10, which is an FAAH inhibitor.
 12. Thepharmaceutical composition according to claim 10, which is a medicamentfor treatment of urinary frequency, urinary incontinence and/oroveractive bladder.
 13. The pharmaceutical composition according toclaim 10, which is a medicament for treatment of pain.
 14. A method,comprising the step of synthesizing a compound that is the pyridylnon-aromatic nitrogen-containing heterocyclic-1-carboxylate compound ofclaim 1 or its pharmaceutically acceptable salt; and using said compoundto make an FAAH inhibitor or a medicament for treating urinaryfrequency, urinary incontinence and/or overactive bladder.
 15. A method,comprising the step of synthesizing a compound that is the pyridylnon-aromatic nitrogen-containing heterocyclic-1-carboxylate compound ofclaim 1 or its pharmaceutically acceptable salt; and using said compoundto make an FAAH inhibitor or a medicament for treating pain.
 16. Amethod for treating urinary frequency, urinary incontinence and/oroveractive bladder, comprising administering a therapeutically effectiveamount of the pyridyl non-aromatic nitrogen-containingheterocyclic-1-carboxylate compound of claim 1 or its pharmaceuticallyacceptable salt to a patient.
 17. A method for treating pain, comprisingadministering a therapeutically effective amount of the pyridylnon-aromatic nitrogen-containing heterocyclic-1-carboxylate compound ofclaim 1 and its pharmaceutically acceptable salt to a patient.